U.S. patent application number 15/769754 was filed with the patent office on 2019-01-03 for oxa-diazaspiro compounds having activity against pain.
The applicant listed for this patent is LABORATORIOS DEL DR. ESTEVE S.A.. Invention is credited to Carlos ALEGRET-MOLINA, Carmen ALMANSA-ROSALES, Marina VIRGILI-BERNADO.
Application Number | 20190002475 15/769754 |
Document ID | / |
Family ID | 54364221 |
Filed Date | 2019-01-03 |
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United States Patent
Application |
20190002475 |
Kind Code |
A1 |
VIRGILI-BERNADO; Marina ; et
al. |
January 3, 2019 |
OXA-DIAZASPIRO COMPOUNDS HAVING ACTIVITY AGAINST PAIN
Abstract
The present invention relates to oxa-diazaspiro compounds having
pharmacological activity towards the sigma (.sigma.) receptor, to
processes of preparation of such compounds, to pharmaceutical
compositions comprising them, and to their use in therapy, in
particular for the treatment of pain.
Inventors: |
VIRGILI-BERNADO; Marina;
(Barcelona, ES) ; ALMANSA-ROSALES; Carmen;
(Barcelona, ES) ; ALEGRET-MOLINA; Carlos;
(Barcelona, ES) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
LABORATORIOS DEL DR. ESTEVE S.A. |
Barcelona |
|
ES |
|
|
Family ID: |
54364221 |
Appl. No.: |
15/769754 |
Filed: |
October 21, 2016 |
PCT Filed: |
October 21, 2016 |
PCT NO: |
PCT/EP2016/001742 |
371 Date: |
April 20, 2018 |
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61P 29/00 20180101;
A61P 25/00 20180101; C07D 498/10 20130101; A61P 43/00 20180101;
A61P 25/04 20180101 |
International
Class: |
C07D 498/10 20060101
C07D498/10 |
Foreign Application Data
Date |
Code |
Application Number |
Oct 23, 2015 |
EP |
15382523.7 |
Claims
1-17. (canceled)
18. A compound of general Formula (I): ##STR00415## wherein R.sub.1
is ##STR00416## m is 1, 2, 3, 4 or 5; n is 0, 1, 2, 3, 4 or 5; p is
0 or 1; q is 0, 1 or 2; r is 0, 1 or 2; X is a bond,
--C(R.sub.xR.sub.x')--, --C(O)--, --O--, --C(O)NR.sub.7--,
--NR.sub.7C(O)-- or --C(O)O--; wherein R.sub.x is selected from the
group consisting of halogen or substituted or unsubstituted
C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl
substituted or unsubstituted C.sub.2-6 alkynyl, and --OR.sub.7;
R.sub.x' is selected from the group consisting of hydrogen, halogen
or substituted or unsubstituted C.sub.1-6 alkyl, substituted or
unsubstituted C.sub.2-6 alkenyl and substituted or unsubstituted
C.sub.2-6 alkynyl; R.sub.7 is selected from the group consisting of
hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted
or unsubstituted C.sub.2-6 alkenyl and substituted or unsubstituted
C.sub.2-6 alkynyl; Y is --CH.sub.2-- or --C(O)--; R.sub.1' is
selected from the group consisting of substituted or unsubstituted
C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl,
substituted or unsubstituted C.sub.2-6 alkynyl, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted aryl and
substituted or unsubstituted heterocyclyl; R.sub.2 is selected from
the group consisting of hydrogen, substituted or unsubstituted
C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl,
substituted or unsubstituted C.sub.2-6 alkynyl, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted aryl and
substituted or unsubstituted heterocyclyl, R.sub.3 is selected from
the group consisting of substituted or unsubstituted C.sub.1-6
alkyl, substituted or unsubstituted C.sub.2-6 alkenyl and
substituted or unsubstituted C.sub.2-6 alkynyl; R.sub.3' is
selected from the group consisting of hydrogen, substituted or
unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted
C.sub.2-6 alkenyl and substituted or unsubstituted C.sub.2-6
alkynyl; or R.sub.3 and R.sub.3', together with the carbon atom to
which they are attached, form a substituted or unsubstituted
cycloalkyl; R.sub.4 and R.sub.4' are independently selected from
the group consisting of hydrogen, substituted or unsubstituted
C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl,
substituted or unsubstituted C.sub.2-6 alkynyl, --CHOR.sub.9 and
--C(O)OR.sub.9; wherein R.sub.9 is selected from the group
consisting of hydrogen, substituted or unsubstituted C.sub.1-9
alkyl, substituted or unsubstituted C.sub.2-9 alkenyl and
substituted or unsubstituted C.sub.2-9 alkynyl; R.sub.5 and
R.sub.5' are independently selected from the group consisting of
hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted
or unsubstituted C.sub.2-6 alkenyl, substituted or unsubstituted
C.sub.2-6 alkynyl, substituted or unsubstituted cycloalkyl,
substituted or unsubstituted aryl, substituted or unsubstituted
heterocyclyl, --CHOR.sub.8 and --C(O)OR.sub.8; wherein R.sub.8 is
selected from hydrogen, substituted or unsubstituted C.sub.1-6
alkyl, substituted or unsubstituted C.sub.2-6 alkenyl and
substituted or unsubstituted C.sub.2-6 alkynyl; or R.sub.5 and
R.sub.5', together with the carbon atom to which they are attached,
form a substituted or unsubstituted cycloalkyl or a substituted or
unsubstituted heterocyclyl; R.sub.6 and R.sub.6' are independently
selected from the group consisting of hydrogen, substituted or
unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted
C.sub.2-6 alkenyl, substituted or unsubstituted C.sub.2-6 alkynyl,
--CHOR.sub.10 and --C(O)OR.sub.10; wherein R.sub.10 is selected
from the group consisting of hydrogen, substituted or unsubstituted
C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl and
substituted or unsubstituted C.sub.2-6 alkynyl; optionally as a
stereoisomer, including enantiomers and diastereomers, a racemate
or a mixture of at least two stereoisomers, including enantiomers
and/or diastereomers, in any mixing ratio, or a corresponding salt
thereof, or a corresponding solvate thereof; with the following
provisos applying: q is not 1 when r is 1; when Y is --C(O)--, then
R.sub.1 is not ##STR00417##
19. The compound according to claim 18, which is a compound of
Formula (I') ##STR00418##
20. The compound according to claim 18, which is a compound of
Formula (I.sup.2'), (I.sup.2a'), (I.sup.2b') or (I.sup.2c')
##STR00419##
21. The compound according to claim 18, which is a compound of
Formula (I.sup.3'), (I.sup.3a'), (I.sup.3b') or (I.sup.3c')
##STR00420##
22. The compound according to claim 18, which is a compound of
Formula (I.sup.4'), (I.sup.4a'), (I.sup.4b') or (I.sup.4c')
##STR00421##
23. The compound according to claim 18, wherein R.sub.1 is selected
from the group consisting of substituted or unsubstituted C.sub.1-6
alkyl and substituted or unsubstituted aryl.
24. The compound according to claim 23, wherein R.sub.1' is
selected from the group consisting of substituted or unsubstituted
methyl, substituted or unsubstituted ethyl or substituted or
unsubstituted phenyl.
25. The compound according to claim 18, wherein R.sub.2 is selected
from the group consisting of substituted or unsubstituted C.sub.1-6
alkyl and substituted or unsubstituted aryl.
26. The compound according to claim 25, wherein R.sub.2 is selected
from the group consisting of substituted or unsubstituted
isopropyl, substituted or unsubstituted isobutyl or substituted or
unsubstituted phenyl.
27. The compound according to claim 18, wherein R.sub.3 and
R.sub.3', together with the carbon atom to which they are attached,
form a substituted or unsubstituted cycloalkyl.
28. The compound according to claim 27, wherein R.sub.3 and
R.sub.3' form a substituted or unsubstituted cyclopropyl.
29. The compound according to claim 18 which is selected from the
group consisting of:
12-ethyl-7-isopentyl-4-oxa-7,12-diazadispiro[2.1.5.3]tridecan-13-one,
12-ethyl-7-phenethyl-4-oxa-7,12-diazadispiro[2.1.5.3]tridecan-13-one,
13-ethyl-8-phenethyl-4-oxa-8,13-diazadispiro[2.1.6.3]tetradecan-14-one,
13-ethyl-8-isopentyl-4-oxa-8,13-diazadispiro[2.1.6.3]tetradecan-14-one,
7-benzyl-10-ethyl-4-oxa-7,10-diazadispiro[2.1.3.3]undecan-11-one,
10-ethyl-7-isopentyl-4-oxa-7,10-diazadispiro[2.1.3.3]undecan-11-one,
7-phenethyl-12-phenyl-4-oxa-7,12-diazadispiro[2.1.5.3]tridecan-13-one,
7-isopentyl-12-phenyl-4-oxa-7,12-diazadispiro[2.1.5.3]tridecan-13-one,
8-phenethyl-13-phenyl-4-oxa-8,13-diazadispiro[2.1.6.3]tetradecan-14-one,
8-isopentyl-13-phenyl-4-oxa-8,13-diazadispiro[2.1.6.3]tetradecan-14-one,
7-benzyl-12-ethyl-4-oxa-7,12-diazadispiro[2.1.5.3]tridecan-13-one,
8-benzyl-13-ethyl-4-oxa-8,13-diazadispiro[2.1.6.3]tetradecan-14-one,
7-benzyl-10-ethyl-4-oxa-7,10-diazadispiro[2.1.3.3]undecan-11-one,
8-benzyl-13-phenyl-4-oxa-8,13-diazadispiro[2.1.6.3]tetradecan-14-one,
7-benzyl-12-phenyl-4-oxa-7,12-diazadispiro[2.1.5.3]tridecan-13-one,
13-ethyl-8-phenethyl-4-oxa-8,13-diazadispiro[2.1.6.3]tetradecane,
7-benzyl-12-ethyl-4-oxa-7,12-diazadispiro[2.1.5.3]tridecane,
12-ethyl-7-phenethyl-4-oxa-7,12-diazadispiro[2.1.5.3]tridecane,
7-phenethyl-12-phenyl-4-oxa-7,12-diazadispiro[2.1.5.3]tridecane,
7-isopentyl-12-phenyl-4-oxa-7,12-diazadispiro[2.1.5.3]tridecane,
8-benzyl-13-phenyl-4-oxa-8,13-diazadispiro[2.1.6.3]tetradecane and
8-phenethyl-13-phenyl-4-oxa-8,13-diazadispiro[2.1.6.3]tetradecane
30. The compound according to claim 18, which is selected from the
group consisting of:
7-benzyl-12-phenyl-4-oxa-7,12-diazadispiro[2.1.5.3]tridecane,
(7-phenethyl-4-oxa-7,12-diazadispiro[2.1.5.3]tridecan-12-yl)(phenyl)metha-
none,
(7-isopentyl-4-oxa-7,12-diazadispiro[2.1.5.3]tridecan-12-yl)(phenyl)-
methanone,
(7-isobutyl-4-oxa-7,12-diazadispiro[2.1.5.3]tridecan-12-yl)(phe-
nyl)methanone,
(8-phenethyl-4-oxa-8,13-diazadispiro[2.1.6.3]tetradecan-13-yl)(phenyl)met-
hanone,
(8-isopentyl-4-oxa-8,13-diazadispiro[2.1.6.3]tetradecan-13-yl)(phe-
nyl)methanone,
(8-isobutyl-4-oxa-8,13-diazadispiro[2.1.6.3]tetradecan-13-yl)(phenyl)meth-
anone,
4-ethyl-2,2-dimethyl-9-phenethyl-1-oxa-4,9-diazaspiro[5.6]dodecan-3-
-one,
4-ethyl-9-isopentyl-2,2-dimethyl-1-oxa-4,9-diazaspiro[5.6]dodecan-3--
one,
4-ethyl-9-isobutyl-2,2-dimethyl-1-oxa-4,9-diazaspiro[5.6]dodecan-3-on-
e,
10-benzyl-7-phenethyl-4-oxa-7,10-diazadispiro[2.1.3.3]undecan-11-one,
(2,2-dimethyl-9-phenethyl-1-oxa-4,9-diazaspiro[5.6]dodecan-4-yl)(phenyl)m-
ethanone,
10-ethyl-7-(2-isopropoxyethyl)-4-oxa-7,10-diazadispiro[2.1.3.3]u-
ndecan-11-one,
(R)-8-ethyl-2-isopentyl-6-methyl-5-oxa-2,8-diazaspiro[3.5]nonan-7-one,
(S)-8-ethyl-2-isopentyl-6-methyl-5-oxa-2,8-diazaspiro[3.5]nonan-7-one,
(R)-8-ethyl-2-isobutyl-6-methyl-5-oxa-2,8-diazaspiro[3.5]nonan-7-one,
(S)-8-ethyl-2-isobutyl-6-methyl-5-oxa-2,8-diazaspiro[3.5]nonan-7-one,
(R)-2-isopentyl-8-isopropyl-6-methyl-5-oxa-2,8-diazaspiro[3.5]nonan-7-one-
,
(S)-2-isopentyl-8-isopropyl-6-methyl-5-oxa-2,8-diazaspiro[3.5]nonan-7-on-
e,
(R)-2-isobutyl-8-isopropyl-6-methyl-5-oxa-2,8-diazaspiro[3.5]nonan-7-on-
e,
(S)-2-isobutyl-8-isopropyl-6-methyl-5-oxa-2,8-diazaspiro[3.5]nonan-7-on-
e,
(S)-2-(3,3-dimethylbutyl)-8-isopropyl-6-methyl-5-oxa-2,8-diazaspiro[3.5-
]nonan-7-one,
(R)-2-(3,3-dimethylbutyl)-8-isopropyl-6-methyl-5-oxa-2,8-diazaspiro[3.5]n-
onan-7-one,
(2R,6S)-4-ethyl-9-isopentyl-2-methy-1-oxa-4,9-diazaspiro[5.6]dodecan-3-on-
e,
(2R,6R)-4-ethyl-9-isopentyl-2-methy-1-oxa-4,9-diazaspiro[5.6]dodecan-3--
one,
(2S,6S)-4-ethyl-9-isopentyl-2-methyl-1-oxa-4,9-diazaspiro[5.6]dodecan-
-3-one,
(2S,6R)-4-ethyl-9-isopentyl-2-methyl-1-oxa-4,9-diazaspiro[5.6]dode-
can-3-one,
(9-(2-isopropoxyethyl)-2,2-dimethyl-1-oxa-4,9-diazaspiro[5.6]do-
decan-4-yl)(phenyl)methanone,
(7-benzyl-4-oxa-7,12-diazadispiro[2.1.5.3]tridecan-12-yl)(phenyl)methanon-
e,
(8-benzyl-4-oxa-8,13-diazadispiro[2.1.6.3]tetradecan-13-yl)(phenyl)meth-
anone,
9-benzyl-4-ethyl-2,2-dimethyl-1-oxa-4,9-diazaspiro[5.6]dodecan-3-on-
e,
4-((4-ethyl-2,2-dimethyl-3-oxo-1-oxa-4,9-diazaspiro[5.6]dodecan-9-yl)me-
thyl)benzonitrile,
(2R,6S)-9-benzyl-4-ethyl-2-methyl-1-oxa-4,9-diazaspiro[5.6]dodecan-3-one,
(2R,6R)-9-benzyl-4-ethyl-2-methyl-1-oxa-4,9-diazaspiro[5.6]dodecan-3-one,
(2S,6S)-9-benzyl-4-ethyl-2-methyl-1-oxa-4,9-diazaspiro[5.6]dodecan-3-one,
(2S,6R)-9-benzyl-4-ethyl-2-methyl-1-oxa-4,9-diazaspiro[5.6]dodecan-3-one,
(2R,6S)-4-ethyl-9-(4-fluorobenzyl)-2-methyl-1-oxa-4,9-diazaspiro[5.6]dode-
can-3-one,
(2R,6R)-4-ethyl-9-(4-fluorobenzyl)-2-methyl-1-oxa-4,9-diazaspir-
o[5.6]dodecan-3-one,
(2S,6S)-4-ethyl-9-(4-fluorobenzyl)-2-methy-1-oxa-4,9-diazaspiro[5.6]dodec-
an-3-one,
(2S,6R)-4-ethyl-9-(4-fluorobenzyl)-2-methy-1-oxa-4,9-diazaspiro[-
5.6]dodecan-3-one,
4-(((2R,6S)-4-ethyl-2-methy-3-oxo-1-oxa-4,9-diazaspiro[5.6]dodecan-9-yl)m-
ethyl)benzonitrile,
4-(((2R,6R)-4-ethyl-2-methyl-3-oxo-1-oxa-4,9-diazaspiro[5.6]dodecan-9-yl)-
methyl)benzonitrile,
4-(((2S,6S)-4-ethyl-2-methyl-3-oxo-1-oxa-4,9-diazaspiro[5.6]dodecan-9-yl)-
methyl)benzonitrile,
4-(((2S,6R)-4-ethyl-2-methyl-3-oxo-1-oxa-4,9-diazaspiro[5.6]dodecan-9-yl)-
methyl)benzonitrile,
8-benzyl-13-methyl-4-oxa-8,13-diazadispiro[2.1.6.3]tetradecan-14-one,
8-(4-fluorobenzyl)-13-methyl-4-oxa-8,13-diazadispiro[2.1.6.3]tetradecan-1-
4-one,
4-((13-methyl-14-oxo-4-oxa-8,13-diazadispiro[2.1.6.3]tetradecan-8-y-
l)methyl)benzonitrile,
(S)-8-ethyl-6-methyl-2-neopentyl-5-oxa-2,8-diazaspiro[3.5]nonan-7-one,
(R)-8-ethyl-6-methyl-2-neopentyl-5-oxa-2,8-diazaspiro[3.5]nonan-7-one,
(S)-8-isopropyl-6-methyl-2-neopentyl-5-oxa-2,8-diazaspiro[3.5]nonan-7-one-
,
(R)-8-isopropyl-6-methyl-2-neopentyl-5-oxa-2,8-diazaspiro[3.5]nonan-7-on-
e, 7,12-dibenzyl-4-oxa-7,12-diazadispiro[2.1.5.3]tridecane(*),
12-benzyl-7-phenethyl-4-oxa-7,12-diazadispiro[2.1.5.3]tridecane(*),
12-benzyl-7-isopentyl-4-oxa-7,12-diazadispiro[2.1.5.3]tridecane(*),
12-benzyl-7-isobutyl-4-oxa-7,12-diazadispiro[2.1.5.3]tridecane(*),
8,13-dibenzyl-4-oxa-8,13-diazadispiro[2.1.6.3]tetradecane(*),
13-benzyl-8-phenethyl-4-oxa-8,13-diazadispiro[2.1.6.3]tetradecane(*),
13-benzyl-8-isopentyl-4-oxa-8,13-diazadispiro[2.1.6.3]tetradecane(*),
13-benzyl-8-isobutyl-4-oxa-8,13-diazadispiro[2.1.6.3]tetradecane(*),
9-benzyl-4-ethyl-2,2-dimethyl-1-oxa-4,9-diazaspiro[5.6]dodecane,
4-ethyl-2,2-dimethyl-9-phenethyl-1-oxa-4,9-diazaspiro[5.6]dodecane,
4-ethyl-9-isopentyl-2,2-dimethyl-1-oxa-4,9-diazaspiro[5.6]dodecane,
4-ethyl-9-isobutyl-2,2-dimethyl-1-oxa-4,9-diazaspiro[5.6]dodecane,
10-benzyl-7-phenethyl-4-oxa-7,10-diazadispiro[2.1.3.3]undecane,
(7-Phenethyl-4-oxa-7,10-diazadispiro[2.1.3.3]undecan-10-yl)(phenyl)methan-
one,
(R)-8-benzyl-13-ethyl-4-oxa-8,13-diazadispiro[2.1.6.3]tetradecan-14-o-
ne,
(S)-8-benzyl-13-ethyl-4-oxa-8,13-diazadispiro[2.1.6.3]tetradecan-14-on-
e,
(R)-(2,2-dimethyl-9-phenethyl-1-oxa-4,9-diazaspiro[5.6]dodecan-4-yl)(ph-
enyl)methanone and
(S)-(2,2-dimethyl-9-phenethyl-1-oxa-4,9-diazaspiro[5.6]dodecan-4-yl)(phen-
yl)methanone.
31. The compound according to claim 18, which is selected from the
group consisting of:
((2S,6R)-9-isopentyl-2-methy-1-oxa-4,9-diazaspiro[5.6]dodecan-4-yl)(pheny-
l)methanone,
((2S,6S)-9-isopentyl-2-methyl-1-oxa-4,9-diazaspiro[5.6]dodecan-4-yl)(phen-
yl)methanone,
((2R,6R)-9-isopentyl-2-methyl-1-oxa-4,9-diazaspiro[5.6]dodecan-4-yl)(phen-
yl)methanone,
((2R,6S)-9-isopentyl-2-methyl-1-oxa-4,9-diazaspiro[5.6]dodecan-4-yl)(phen-
yl)methanone,
(R)-(8-isopentyl-4-oxa-8,13-diazadispiro[2.1.6.3]tetradecan-13-yl)(phenyl-
)methanone and
(S)-(8-isopentyl-4-oxa-8,13-diazadispiro[2.1.6.3]tetradecan-13-yl)(phenyl-
)methanone.
32. A process for the preparation of the compound according to
claim 18, wherein R.sub.1 is --(CR.sub.4R.sub.4').sub.pR.sub.1',
which process comprises: a) an intramolecular cyclization of a
compound of formula VIIa ##STR00422## wherein LG represents a
leaving group, including halogen, mesylate, tosylate and triflate,
with the proviso that when Y.dbd.CO, LG represents chloro or bromo,
or b) the reaction of a compound of formula VIIIH ##STR00423## with
a compound of formula IX, X or XI, ##STR00424## wherein LG
represents a leaving group, including halogen, mesylate, tosylate
and triflate, or c1) when Y is CH.sub.2, by the alkylation of a
compound of formula XIV ##STR00425## with a compound of formula XV
##STR00426## wherein the compound of formula XV is an alkylating
agent and V is a leaving group, or alternatively by the reductive
amination reaction of a compound of formula XIV with a compound of
formula XV, wherein the compound of formula XV is an aldehyde and V
is a C(O)H group; or c2) when Y is C(O), by the alkylation of a
compound of formula XIV ##STR00427## with a compound of formula XV
##STR00428## wherein the compound of formula XV is an alkylating
agent and V is a leaving group, and wherein R.sub.1', R.sub.2,
R.sub.3, R.sub.3', R.sub.4, R.sub.4', R.sub.5, R.sub.5', R.sub.6,
R.sub.6', R.sub.7, R.sub.8, R.sub.9, R.sub.10, R.sub.x, R.sub.x',
X, Y, m, n, p, q and r have the meanings as defined in claim 18 for
the compound of Formula (I).
33. A process for the preparation of the compound according to
claim 18, wherein R.sub.1 is --(CR.sub.4R.sub.4').sub.pR.sub.1', Y
represents CO and R.sub.3 and R.sub.3', together with the carbon
atom to which they are attached, form a cyclopropyl (compounds of
formula Id), ##STR00429## which process comprises a) the treatment
with a strong base of a compound of formula Ic wherein
R.sub.s.dbd.R.sub.s'.dbd.H and s=1 ##STR00430## wherein LG
represents a leaving group, including halogen, mesylate, tosylate
and triflate, or b) a cyclopropanation reaction on a compound of
formula XXXI ##STR00431## or c) the alkylation of a compound of
formula XXV ##STR00432## with a compound of formula XV ##STR00433##
wherein the compound of formula XV is an alkylating agent and V is
a leaving group; or d) the reaction of a compound of formula XIXH
##STR00434## with a compound of formula IX, X or XI, ##STR00435##
wherein LG is a leaving group, including halogen, mesylate,
tosylate and triflate, and wherein R.sub.1', R.sub.2, R.sub.4,
R.sub.4', R.sub.5, R.sub.5', R.sub.6, R.sub.6', R.sub.7, R.sub.8,
R.sub.9, R.sub.10, R.sub.x, R.sub.x', X, m, n, p, q and r have the
meanings as defined in claim 18 for the compound of Formula
(I).
34. A process for the preparation of the compound of Formula (I)
according to claim 18, employing a compound of Formula II, IIP,
III, IIIP, IVa, IVb, Vb, VbP, XII, XIIP, Va, VaP, VI, VIIb, VIIbP,
XIII, XIIIP, Vila, VIIaP, XVI, XVIP, XVIH, XIV, XIVP, XIVH, la,
VIIIP, VIIIH, XV, IX, X, XI, Ie, XXP, XXH, XXI, XXIP, XXIH, Ib,
XVIIP, XVIIH, Ic, XVIIIP, Id, XIXP, XIXH, XXIII, XIIIP, XIIIH, XXV,
XXVP, XXVH, XXII, XXIIP, XXIIH, XXIV, XXIVP, XXIVH, If, XXVIP,
XXVIH, XXVIIa, Ig, XXVIIIP, XXVIIH, XXVIIb, Ih, XXIXP, XXIXH,
XXVIIc, Ib, XVIIP, XVIIH, XXXII, XXXIIP, XXXIIH, XXXIV, XXXIVP,
XXXIVH, XXXI, XXXIP, XXXIH, XXXIII, XXXIIIP, XXXIIIH, XXXV, Ij,
XXXVIP, XXXVIH, Ih, XXIXP, XXIXH, Ii, XXXP or XXXH, ##STR00436##
##STR00437## ##STR00438## ##STR00439## ##STR00440## ##STR00441##
##STR00442## wherein R.sub.1, R.sub.2, R.sub.3, R.sub.3', R.sub.4,
R.sub.4', R.sub.5, R.sub.5', R.sub.6, R.sub.6', R.sub.7, R.sub.8,
R.sub.9, R.sub.10, R.sub.x, R.sub.x', X, Y, m, n, p, q and r have
the meanings as defined in claim 18 for the compound of Formula
(I), LG represents a leaving group, including halogen, mesylate,
tosylate and triflate, V represents an aldehyde or a leaving group,
including halogen, mesylate, tosylate and triflate, P represents a
suitable protecting group, including Boc, P' represents an
orthogonal protecting group, including 4-methoxybenzyl, benzyl and
benzhydryl, X' represents a leaving group, including halogen,
mesylate, tosylate and triflate, Q represents methyl or benzyl, Z
represents OH or halogen, including bromo and chloro, R.sub.s and
R.sub.s' represent hydrogen or alkyl and s represents 1, 2, 3 or
4.
35. A pharmaceutical composition which comprises the compound
according to claim 18, or a pharmaceutically acceptable salt
thereof, and a pharmaceutically acceptable carrier, adjuvant or
vehicle
36. A method of treating pain in a subject in need thereof,
comprising administration of an effective amount of the compound
according to claim 18.
37. The method according to claim 36, wherein the pain, is selected
from the group consisting of medium to severe pain, visceral pain,
chronic pain, cancer
Description
FIELD OF THE INVENTION
[0001] The present invention relates to new oxa-diazaspiro
compounds having affinity for sigma receptors, especially sigma-1
(.sigma..sub.1) receptors, as well as to the process for the
preparation thereof, to compositions comprising them, and to their
use as medicaments.
BACKGROUND OF THE INVENTION
[0002] The search for new therapeutic agents has been greatly aided
in recent years by better understanding of the structure of
proteins and other biomolecules associated with target diseases.
One important class of these proteins are the sigma (.sigma.)
receptors, cell surface receptors of the central nervous system
(CNS) which may be related to the dysphoric, hallucinogenic and
cardiac stimulant effects of opioids. From studies of the biology
and function of sigma receptors, evidence has been presented that
sigma receptor ligands may be useful in the treatment of psychosis
and movement disorders such as dystonia and tardive dyskinesia, and
motor disturbances associated with Huntington's chorea or
Tourette's syndrome and in Parkinson's disease (Walker, J. M. et
al, Pharmacological Reviews, 1990, 42, 355). It has been reported
that the known sigma receptor ligand rimcazole clinically shows
effects in the treatment of psychosis (Snyder, S. H., Largent, B.
L. J. Neuropsychiatry 1989, 1, 7). The sigma binding sites have
preferential affinity for the dextrorotatory isomers of certain
opiate benzomorphans, such as (+)SKF-10047, (+)cyclazocine, and
(+)-pentazocine and also for some narcoleptics such as
haloperidol.
[0003] "The sigma receptor/s" as used in this application is/are
well known and defined using the following citation: This binding
site represents a typical protein different from opioid, NMDA,
dopaminergic, and other known neurotransmitter or hormone receptor
families (G. Ronsisvalle et al. Pure Appl. Chem. 73, 1499-1509
(2001)).
[0004] The sigma receptor has at least two subtypes, which may be
discriminated by stereoselective isomers of these pharmacoactive
drugs. (+)SKF-10047 has nanomolar affinity for the sigma-1
(.sigma..sub.1) site, and has micromolar affinity for the sigma-2
(.sigma..sub.2) site. Haloperidol has similar affinities for both
subtypes.
[0005] The .sigma..sub.1 receptor is a non-opiaceous type receptor
expressed in numerous adult mammal tissues (e.g. central nervous
system, ovary, testicle, placenta, adrenal gland, spleen, liver,
kidney, gastrointestinal tract) as well as in embryo development
from its earliest stages, and is apparently involved in a large
number of physiological functions. Its high affinity for various
pharmaceuticals has been described, such as for (+)SKF-10047,
(+)-pentazocine, haloperidol and rimcazole, among others, known
ligands with analgesic, anxiolytic, antidepressive, antiamnesic,
antipsychotic and neuroprotective activity. .sigma..sub.1 receptor
is of great interest in pharmacology in view of its possible
physiological role in processes related to analgesia, anxiety,
addiction, amnesia, depression, schizophrenia, stress,
neuroprotection and psychosis [Kaiser et al (1991)
Neurotransmissions 7 (1): 1-5], [Walker, J. M. et al,
Pharmacological Reviews, 1990, 42, 355] and [Bowen W. D. (2000)
Pharmaceutica Acta Helvetiae 74: 211-218].
[0006] The .sigma..sub.2 receptor is also expressed in numerous
adult mammal tissues (e.g. nervous system, immune system, endocrine
system, liver, kidney). .sigma..sub.2 receptors can be components
in a new apoptosis route that may play an important role in
regulating cell proliferation or in cell development. This route
seems to consist of .sigma..sub.2 receptors joined to intracellular
membranes, located in organelles storing calcium, such as the
endoplasmic reticulum and mitochondria, which also have the ability
to release calcium from these organelles. The calcium signals can
be used in the signaling route for normal cells and/or in induction
of apoptosis.
[0007] Agonists of .sigma..sub.2 receptors induce changes in cell
morphology, apoptosis in several types of cell lines and regulate
the expression of p-glycoprotein mRNA, so that they are potentially
useful as antineoplasic agents for treatment of cancer. In fact,
.sigma..sub.2 receptor agonists have been observed to induce
apoptosis in mammary tumour cell lines resistant to common
antineoplasic agents that damage DNA. In addition, agonists of
.sigma..sub.2 receptors enhance the cytotoxic effects of these
antineoplasic agents at concentrations in which the agonist is not
cytotoxic. Thus, agonists of .sigma..sub.2 receptors can be used as
antineoplasic agents at doses inducing apoptosis or at sub-toxic
doses in combination with other antineoplasic agents to revert the
resistance to the drug, thereby allowing using lower doses of the
antineoplasic agent and considerably reducing its adverse
effects.
[0008] Antagonists of .sigma..sub.2 receptors can prevent the
irreversible motor side effects caused by typical neuroleptic
agents. In fact, it has been found that antagonists of
.sigma..sub.2 receptors can be useful as agents for improving the
weakening effects of delayed dyskinesia appearing in patients due
to chronic treatment of psychosis with typical antipsychotic drugs,
such as haloperidol. .sigma..sub.2 receptors also seem to play a
role in certain degenerative disorders in which blocking these
receptors could be useful.
[0009] Endogenous sigma ligands are not known, although
progesterone has been suggested to be one of them. Possible
sigma-site-mediated drug effects include modulation of glutamate
receptor function, neurotransmitter response, neuroprotection,
behavior, and cognition (Quirion, R. et al. Trends Pharmacol. Sci.,
1992, 13:85-86). Most studies have implied that sigma binding sites
(receptors) are plasmalemmal elements of the signal transduction
cascade. Drugs reported to be selective sigma ligands have been
evaluated as antipsychotics (Hanner, M. at al. Proc. Natl. Acad.
Sci., 1996, 93:8072-8077). The existence of sigma receptors in the
CNS, immune and endocrine systems have suggested a likelihood that
it may serve as link between the three systems.
[0010] In view of the potential therapeutic applications of
agonists or antagonists of the sigma receptor, a great effort has
been directed to find selective ligands. Thus, the prior art
discloses different sigma receptor ligands.
[0011] For instance, the international patent application
WO2007/098961 describes 4,5,6,7 tetrahydrobenzo[b]thiophene
derivatives having pharmacological activity towards the sigma
receptor.
[0012] Spiro[benzopyran] or spiro[benzofuran] derivatives were also
disclosed in EP1847542 as well as pyrazole derivatives (EP1634873)
with pharmacological activity on sigma receptors.
[0013] WO20091071657 discloses some tricyclic triazolic compounds
although structurally different to the ones of the current
invention with activity towards sigma receptors.
[0014] Nevertheless, there is still a need to find compounds having
pharmacological activity towards the sigma receptor, being both
effective, selective, and/or having good "drugability" properties,
i.e. good pharmaceutical properties related to administration,
distribution, metabolism and excretion.
[0015] Surprisingly, it has been observed that the new
oxa-diazaspiro compounds with general Formula (I) show a selective
affinity for .sigma..sub.1 receptor ranging from good to excellent.
These compounds are therefore particularly suitable as
pharmacologically active agents in medicaments for the prophylaxis
and/or treatment of disorders or diseases related to Sigma
receptors.
SUMMARY OF THE INVENTION
[0016] The present invention discloses novel compounds with great
affinity to sigma receptors and having high solubility in a
physiological media which might be used for the treatment of sigma
related disorders or diseases.
[0017] As this invention is aimed at providing a compound or a
chemically related series of compounds which act as ligands of the
.sigma..sub.1 receptor it is a very preferred embodiment if the
compound has a binding expressed as K.sub.i which is preferably
<1000 nM, more preferably <500 nM, even more preferably
<100 nM.
[0018] The invention is directed in a main aspect to a compound of
general Formula (I)
##STR00001## [0019] wherein R.sub.1, R.sub.2, R.sub.3, R.sub.3',
R.sub.5, R.sub.5', R.sub.6, R.sub.6', X, Y, m, n, q and r areas
defined below in the detailed description.
[0020] A further object of the invention refers to the processes
for preparation of compounds of general formula (I).
[0021] A still further object of the invention refers to the use of
intermediate compounds for the preparation of a compound of general
formula (I).
[0022] It is also an object of the invention a pharmaceutical
composition comprising a compound of formula (I).
[0023] Finally, it is an object of the invention the use of
compound as a medicament and more particularly for the treatment of
pain and pain related conditions.
DETAILED DESCRIPTION OF THE INVENTION
[0024] The present invention discloses novel compounds with great
affinity to sigma receptors and having high solubility in a
physiological media which might be used for the treatment of sigma
related disorders or diseases.
[0025] As this invention is aimed at providing a compound or a
chemically related series of compounds which act as ligands of the
.sigma..sub.1 receptor it is a very preferred embodiment if the
compound has a binding expressed as K.sub.i which is preferably
<1000 nM, more preferably <500 nM, even more preferably
<100 nM.
[0026] Advantageously, the compounds according to the present
invention would in addition show one or more the following
functionalities: .sigma..sub.1 receptor antagonism. It has to be
noted, though, that the functionalities "antagonism" and "agonism"
are also sub-divided in their effect into subfunctionalities like
partial agonism or inverse agonism. Accordingly, the
functionalities of the compound should be considered within a
relatively broad bandwidth.
[0027] An antagonist blocks or dampens agonist-mediated responses.
Known subfunctionalities are neutral antagonists or inverse
agonists.
[0028] An agonist increases the activity of the receptor above its
basal level. Known subfunctionalities are full agonists, or partial
agonists.
[0029] The invention is directed in a main aspect to a compound of
general Formula (I),
[0030] In a particular aspect, the present invention is directed to
compounds of general Formula (I):
##STR00002##
wherein
R.sub.1 is
##STR00003##
[0031] m is 1, 2, 3, 4 or 5; n is 0, 1, 2, 3, 4 or 5; p is 0 or 1;
q is 0, 1 or 2; r is 0, 1 or 2; X is a bond,
--C(R.sub.xR.sub.x')--, --C(O)--, --O--, --C(O)NR.sub.7--,
--NR.sub.7C(O)-- or --C(O)O--; [0032] wherein R.sub.x is selected
from halogen or substituted or unsubstituted C.sub.1-6 alkyl,
substituted or unsubstituted C.sub.2-6 alkenyl substituted or
unsubstituted C.sub.2-6 alkynyl, and --OR.sub.7; [0033] R.sub.x' is
selected from hydrogen, halogen or substituted or unsubstituted
C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl and
substituted or unsubstituted C.sub.2-6 alkynyl; [0034] R.sub.7 is
selected from hydrogen, substituted or unsubstituted C.sub.1-6
alkyl, substituted or unsubstituted C.sub.2-6 alkenyl and
substituted or unsubstituted C.sub.2-6 alkynyl;
Y is --CH.sub.2-- or --C(O)--;
[0035] R.sub.1' is selected from substituted or unsubstituted
C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl,
substituted or unsubstituted C.sub.2-6 alkynyl, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted aryl and
substituted or unsubstituted heterocyclyl; R.sub.2 is selected from
hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted
or unsubstituted C.sub.2-6 alkenyl, substituted or unsubstituted
C.sub.2-6 alkynyl, substituted or unsubstituted cycloalkyl,
substituted or unsubstituted aryl and substituted or unsubstituted
heterocyclyl, R.sub.3 is selected from substituted or unsubstituted
C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl and
substituted or unsubstituted C.sub.2-6 alkynyl; R.sub.3' is
selected from hydrogen, substituted or unsubstituted C.sub.1-6
alkyl, substituted or unsubstituted C.sub.2-6 alkenyl and
substituted or unsubstituted C.sub.2-6 alkynyl; alternatively,
R.sub.3 and R.sub.3' may form together with the carbon atom to
which they are attached a substituted or unsubstituted cycloalkyl;
R.sub.4 and R.sub.4' are independently selected from hydrogen,
substituted or unsubstituted C.sub.1-6 alkyl, substituted or
unsubstituted C.sub.2-6 alkenyl, substituted or unsubstituted
C.sub.2-6 alkynyl, --CHOR.sub.9 and --C(O)OR.sub.9; [0036] wherein
R.sub.9 is selected from hydrogen, substituted or unsubstituted
C.sub.1-9 alkyl, substituted or unsubstituted C.sub.2-9 alkenyl and
substituted or unsubstituted C.sub.2-9 alkynyl; R.sub.5 and
R.sub.5' are independently selected from hydrogen, substituted or
unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted
C.sub.2-6 alkenyl, substituted or unsubstituted C.sub.2-6 alkynyl,
substituted or unsubstituted cycloalkyl, substituted or
unsubstituted aryl, substituted or unsubstituted heterocyclyl,
--CHOR.sub.8 and --C(O)OR.sub.8; [0037] wherein R.sub.8 is selected
from hydrogen, substituted or unsubstituted C.sub.1-6 alkyl,
substituted or unsubstituted C.sub.2-6 alkenyl and substituted or
unsubstituted C.sub.2-6 alkynyl; alternatively R.sub.5 and R.sub.5'
taken together with the connecting C-atom may form a substituted or
unsubstituted cycloalkyl or a substituted or unsubstituted
heterocyclyl; R.sub.6 and R.sub.6' are independently selected from
hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted
or unsubstituted C.sub.2-6 alkenyl, substituted or unsubstituted
C.sub.2-5 alkynyl, --CHOR.sub.10 and --C(O)OR.sub.10; [0038]
wherein R.sub.10 is selected from hydrogen, substituted or
unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted
C.sub.2-6 alkenyl and substituted or unsubstituted C.sub.2-6
alkynyl;
[0039] These compounds according to the invention are optionally in
form of one of the stereoisomers, preferably enantiomers or
diastereomers, a racemate or in form of a mixture of at least two
of the stereoisomers, preferably enantiomers and/or diastereomers,
in any mixing ratio, or a corresponding salt thereof, or a
corresponding solvate thereof.
[0040] In another embodiment, these compounds according to the
invention are optionally in form of one of the stereoisomers,
preferably enantiomers or diastereomers, a racemate or in form of a
mixture of at least two of the stereoisomers, preferably
enantiomers and/or diastereomers, in any mixing ratio, or a
corresponding salt thereof.
[0041] In a further embodiment the following proviso applies:
[0042] q is not 1 when r is 1;
[0043] In a further embodiment the following proviso applies:
[0044] when Y is --C(O)--, then R.sub.1 is not
##STR00004##
[0045] In a further embodiment the compound according to the
invention of general Formula (I) is a compound of general Formula
(I')
##STR00005##
wherein, R.sub.1, R.sub.2, R.sub.3, R.sub.3', R.sub.5, R.sub.5', X,
Y, m, q and r are as defined in the description.
[0046] In a further embodiment the compound according to the
invention of general Formula (I) is a compound of general Formula
(I.sup.2')
##STR00006##
wherein R.sub.1, R.sub.2, R.sub.5, R.sub.5', X, Y, m, q and r are
as defined in the description.
[0047] In a further embodiment the compound according to the
invention of general Formula (I) is a compound of general Formula
(I.sup.2a')
##STR00007##
wherein R.sub.1, R.sub.2, R.sub.5, R.sub.5', X, Y, m, q and r are
as defined in the description.
[0048] In a further embodiment the compound according to the
invention of general Formula (I) is a compound of general Formula
(I.sup.2b')
##STR00008##
wherein R.sub.1, R.sub.2, R.sub.5, R.sub.5', X, Y, m, q and r are
as defined in the description.
[0049] In a further embodiment the compound according to the
invention of general Formula (I) is a compound of general Formula
(I.sup.2c')
##STR00009##
wherein R.sub.1, R.sub.2, R.sub.5, R.sub.5', X, Y, m, q and r are
as defined in the description.
[0050] In a further embodiment, for compounds of general Formula
(I) are compounds of general Formula (I.sup.3')
##STR00010##
wherein R.sub.1, R.sub.2, R.sub.5, R.sub.5', m, q and r are as
defined in the description.
[0051] In a further embodiment, for compounds of general Formula
(I) are compounds of general Formula (I.sup.3a')
##STR00011##
wherein R.sub.1, R.sub.2, R.sub.5, R.sub.5', m, q and r are as
defined in the description.
[0052] In a further embodiment, for compounds of general Formula
(I) are compounds of general Formula (I.sup.3b')
##STR00012##
wherein R.sub.1, R.sub.2, R.sub.5, R.sub.5', m, q and r are as
defined in the description.
[0053] In a further embodiment, for compounds of general Formula
(I) are compounds of general Formula (I.sup.3')
##STR00013##
wherein R.sub.1, R.sub.2, R.sub.5, R.sub.5', m, q and r are as
defined in the description.
[0054] In a further embodiment, for compounds of general Formula
(I) are compounds of general Formula (I.sup.4')
##STR00014##
wherein R.sub.1, R.sub.2, R.sub.5, R.sub.5', m, q and r are as
defined in the description.
[0055] In a further embodiment, for compounds of general Formula
(I) are compounds of general Formula (I.sup.4a')
##STR00015##
wherein R.sub.1, R.sub.2, R.sub.5, R.sub.5', m, q and r are as
defined in the description.
[0056] In a further embodiment, for compounds of general Formula
(I) are compounds of general Formula (I.sup.4b')
##STR00016##
wherein R.sub.1, R.sub.2, R.sub.5, R.sub.5', m, q and r are as
defined in the description.
[0057] In a further embodiment, for compounds of general Formula
(I) are compounds of general Formula (I.sup.4c')
##STR00017##
wherein R.sub.1, R.sub.2, R.sub.5, R.sub.5', m, q and r are as
defined in the description.
[0058] In a further embodiment, for compounds of general Formula
(I) are compounds of general Formula (I.sup.5')
##STR00018##
wherein R.sub.1', R.sub.2, R.sub.4, R.sub.4' R.sub.5, R.sub.5', Y,
m, p, q and r are as defined in the description.
[0059] In a further embodiment, for compounds of general Formula
(I) are compounds of general Formula (I.sup.5a')
##STR00019##
wherein R.sub.1', R.sub.2, R.sub.4, R.sub.4' R.sub.5, R.sub.5', Y,
m, p, q and r are as defined in the description.
[0060] In a further embodiment, for compounds of general Formula
(I) are compounds of general Formula (I.sup.5b')
##STR00020##
wherein R.sub.1', R.sub.2, R.sub.4, R.sub.4' R.sub.5, R.sub.5', Y,
m, p, q and r are as defined in the description.
[0061] In a further embodiment, for compounds of general Formula
(I) are compounds of general Formula (I.sup.5c')
##STR00021##
wherein R.sub.1', R.sub.2, R.sub.4, R.sub.4' R.sub.5, R.sub.5', R
Y, m, p, q and r are as defined in the description.
[0062] For clarity purposes, reference is also made to the
following statements below in the definitions of substitutions on
alkyl etc. or aryl etc. that "wherein when different radicals
R.sub.1 to R.sub.14'''' and R.sub.x, R.sub.x' are present
simultaneously in Formula I they may be identical or different".
This statement is reflected in the below general Formula (I.sup.6')
being derived from and falling into general Formula (I) as well as
Formula (I).
##STR00022##
wherein R.sub.1, R.sub.2, R.sub.3, R.sub.3', R.sub.5, R.sub.5', X,
Y, q and r are as defined in the description. In addition, m'
(being 0 or 1), R.sub.5'' and R.sub.5''' are added. As said above,
this statement is thus reflected in that R.sub.5'' and R.sub.5'''
are or could be different from R.sub.5 and R.sub.5' or not
and--accordingly--m' being 0 or 1 is naturally resulting from m (in
general Formula (I) being 1 or 2).
[0063] The same would be applicable mutatis mutandis for general
Formulas like general Formula (I) as well as the other general
Formulas (I') to (I.sup.5c') above as well as to all the
intermediates of synthesis.
[0064] For clarity purposes, all groups and definitions described
in the description and referring to compounds of general Formula
(I), also apply to compounds of general Formula (I'), (I.sup.2'),
(I.sup.3'), (I.sup.4'), (I.sup.5'), (I.sup.2a'), (I.sup.3a'),
(I.sup.4a'), (I.sup.5a'), (I.sup.2b'), (I.sup.3b'), (I.sup.4b'),
(I.sup.5b'), (I.sup.2c'), (I.sup.3c'), (I.sup.4c'), (I.sup.5c') and
also (I.sup.6') as well as to all the intermediates of synthesis,
when those groups are present in the mentioned general Markush
formulae, since compounds of general Formula (I'), (I.sup.2'),
(I.sup.3'), (I.sup.4'), (I.sup.5'), (I.sup.2a'), (I.sup.3a'),
(I.sup.4a'), (I.sup.5a'), (I.sup.2b'), (I.sup.3b'), (I.sup.4b'),
(I.sup.5b'), (I.sup.2c'), (I.sup.3c'), (I.sup.4c'), (I.sup.5c') or
(I.sup.6') are included in the general Formula (I).
[0065] For clarity purposes, the general Markush Formula (I)
##STR00023##
is equivalent to wherein only-C(R.sub.5R.sub.5')-- and
--C(R.sub.6R.sub.6')-- are included into the brackets and m and n
mean the number of times that --C(R.sub.5R.sub.5')-- and
--C(R.sub.6R.sub.6')-- are repeated, respectively. The same would
apply to general Markush Formulae (I'), (I.sup.2'), (I.sup.3'),
(I.sup.4'), (I.sup.5'), (I.sup.2a'), (I.sup.3a'), (I.sup.4a'),
(I.sup.5a'), (I.sup.2b'), (I.sup.3b'), (I.sup.4b'), (I.sup.5b'),
(I.sup.2c'), (I.sup.3c'), (I.sup.4c'), (I.sup.5c') or (I.sup.6') as
well as to all the intermediates of synthesis.
[0066] In addition, and for clarity purposes, it should further be
understood that naturally if m or n are 0, then X or R.sub.2 are
still present in general Markush Formulae (I'), (I.sup.2'),
(I.sup.3'), (I.sup.4'), (I.sup.5'), (I.sup.2a'), (I.sup.3a'),
(I.sup.4a'), (I.sup.5a'), (I.sup.2b'), (I.sup.3b'), (I.sup.4b'),
(I.sup.5b'), (I.sup.2c'), (I.sup.3c'), (I.sup.4c'), (I.sup.5c') or
(I.sup.6') as well as to all the intermediates of synthesis.
[0067] In the context of this invention, alkyl is understood as
meaning saturated, linear or branched hydrocarbons, which may be
unsubstituted or substituted once or several times. It encompasses
e.g. --CH.sub.3 and --CH.sub.2--CH.sub.3. In these radicals,
C.sub.1-2-alkyl represents C1- or C2-alkyl, C.sub.1-3-alkyl
represents C1-, C2- or C3-alkyl, C.sub.1-4-alkyl represents C1-,
C2-, C3- or C4-alkyl, C.sub.1-5-alkyl represents C1-, C2-, C3-,
C4-, or C5-alkyl, C.sub.1-6-alkyl represents C1-, C2-, C3-, C4-,
C5- or C6-alkyl, C.sub.1-7-alkyl represents C1-, C2-, C3-, C4-,
C5-, C6- or C7-alkyl, C.sub.1-8-alkyl represents C1-, C2-, C3-,
C4-, C5-, C6-, C7- or C8-alkyl, C.sub.1-10-alkyl represents C1-,
C2-, C3-, C4-, C5-, C6-, C7-, C8-, C9- or C10-alkyl and
C.sub.1-18-alkyl represents C1-, C2-, C3-, C4-, C5-, C6-, C7-, C8-,
C9-, C10-, C11-, C12-, C13-, C14-, C15-, C16-, C17- or C18-alkyl.
The alkyl radicals are preferably methyl, ethyl, propyl,
methylethyl, butyl, 1-methylpropyl, 2-methylpropyl,
1,1-dimethylethyl, pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl,
2,2-dimethylpropyl, hexyl, 1-methylpentyl, if substituted also
CHF.sub.2, CF.sub.3 or CH.sub.2OH etc. Preferably alkyl is
understood in the context of this invention as C.sub.1-8alkyl like
methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, or octyl;
preferably is C.sub.1-6alkyl like methyl, ethyl, propyl, butyl,
pentyl, or hexyl; more preferably is C.sub.1-4 alkyl like methyl,
ethyl, propyl or butyl.
[0068] Alkenyl is understood as meaning unsaturated, linear or
branched hydrocarbons, which may be unsubstituted or substituted
once or several times. It encompasses groups like e.g.
--CH.dbd.CH--CH.sub.3. The alkenyl radicals are preferably vinyl
(ethenyl), allyl (2-propenyl). Preferably in the context of this
invention alkenyl is C.sub.2-10-alkenyl or C.sub.2-8-alkenyl like
ethylene, propylene, butylene, pentylene, hexylene, heptylene or
octylene; or is C.sub.2-6-alkenyl like ethylene, propylene,
butylene, pentylene, or hexylene; or is C.sub.2-4-alkenyl, like
ethylene, propylene, or butylenes.
[0069] Alkynyl is understood as meaning unsaturated, linear or
branched hydrocarbons, which may be unsubstituted or substituted
once or several times. It encompasses groups like e.g.
--C.ident.C--CH.sub.3 (1-propinyl). Preferably alkynyl in the
context of this invention is C.sub.2-10-alkynyl or
C.sub.2-8-alkynyl like ethyne, propyne, butyene, pentyne, hexyne,
heptyne, or octyne; or is C.sub.2-6-alkynyl like ethyne, propyne,
butyene, pentyne, or hexyne; or is C.sub.2-4-alkynyl like ethyne,
propyne, butyene, pentyne, or hexyne.
[0070] In connection with alkyl (also in alkylaryl,
alkylheterocycyl or alkylcycloalkyl), alkenyl, alkynyl and
O-alkyl--unless defined otherwise--the term substituted in the
context of this invention is understood as meaning replacement of
at least one hydrogen radical on a carbon atom by halogen (F, Cl,
Br, I), --NR.sub.cR.sub.c''', --SR.sub.c, --S(O)R.sub.c,
--S(O).sub.2R.sub.c, --OR.sub.c, --C(O)OR.sub.c, --CN,
--C(O)NR.sub.cR.sub.c', haloalkyl, haloalkoxy or --OC.sub.1-6alkyl,
being R.sub.c represented by R.sub.11, R.sub.12, R.sub.13, (being
R.sub.c' represented by R.sub.11', R.sub.12', R.sub.13'; being
R.sub.c'' represented by R.sub.11'', R.sub.12'', R.sub.13''; being
R.sub.c''' represented by R.sub.11''', R.sub.12''', R.sub.13''',
being R.sub.c'''' represented by R.sub.11'''', R.sub.12'''',
R.sub.13'''') wherein R.sub.1 to R.sub.14'''' and R.sub.x and
R.sub.x' are as defined in the description, and wherein when
different radicals R.sub.1 to R.sub.14'''' and R.sub.x and R.sub.x'
are present simultaneously in Formula I they may be identical or
different.
[0071] Most preferably in connection with alkyl (also in alkylaryl,
alkylheterocyclyl or alkylcycloalkyl), alkenyl, alkynyl or O-alkyl,
substituted is understood in the context of this invention that any
alkyl (also in alkylaryl, alkylheterocyclyl or alkylcycloalkyl),
alkenyl, alkynyl or O-alkyl which is substituted is substituted
with one or more of halogen (F, Cl, Br, I), --OR.sub.c, --CN,
--NR.sub.cR.sub.c''', haloalkyl, haloalkoxy or --OC.sub.1-6alkyl
being R.sub.c represented by R.sub.11, R.sub.12, R.sub.13, (being
R.sub.c' represented by R.sub.11', R.sub.12', R.sub.13'; being
R.sub.c'' represented by R.sub.11'', R.sub.12'', R.sub.13''' being
R.sub.c''' represented by R.sub.11''', R.sub.12''', R.sub.13''',
being R.sub.c'''' represented by R.sub.11'''', R.sub.12'''',
R.sub.13''''), wherein R.sub.1 to R.sub.14'''' and R.sub.x and
R.sub.x' are as defined in the description, and wherein when
different radicals R.sub.1 to R.sub.14'''' and R.sub.x and R.sub.x'
are present simultaneously in Formula I, they may be identical or
different.
[0072] More than one replacement on the same molecule and also on
the same carbon atom is possible with the same or different
substituents. This includes for example 3 hydrogens being replaced
on the same C atom, as in the case of CF.sub.3, or at different
places of the same molecule, as in the case of e.g.
--CH(OH)--CH.dbd.CH--CHCl.sub.2.
[0073] In the context of this invention haloalkyl is understood as
meaning an alkyl being substituted once or several times by a
halogen (selected from F, Cl, Br, I). It encompasses e.g.
--CH.sub.2Cl, --CH.sub.2F, --CHCl.sub.2, --CHF.sub.2, --CCl.sub.3,
--CF.sub.3 and --CH.sub.2--CHCl.sub.2. Preferably haloalkyl is
understood in the context of this invention as halogen-substituted
C.sub.1-4-alkyl representing halogen substituted C1-, C2-, C3- or
C4-alkyl. The halogen-substituted alkyl radicals are thus
preferably methyl, ethyl, propyl, and butyl. Preferred examples
include --CH.sub.2Cl, --CH.sub.2F, --CHCl.sub.2, --CHF.sub.2, and
--CF.sub.3.
[0074] In the context of this invention haloalkoxy is understood as
meaning an --O-- alkyl being substituted once or several times by a
halogen (selected from F, Cl, Br, I). It encompasses e.g.
--OCH.sub.2Cl, --OCH.sub.2F, --OCHCl.sub.2, --OCHF.sub.2,
--OCCl.sub.3, --OCF.sub.3 and --OCH.sub.2--CHCl.sub.2. Preferably
haloalkyl is understood in the context of this invention as
halogen-substituted --OC.sub.1-4-alkyl representing halogen
substituted C1-, C2-, C3- or C4-alkoxy. The halogen-substituted
alkyl radicals are thus preferably O-methyl, O-ethyl, O-propyl, and
O-butyl. Preferred examples include --OCH.sub.2Cl, --OCH.sub.2F,
--OCHCl.sub.2, --OCHF.sub.2, and --OCF.sub.3.
[0075] In the context of this invention cycloalkyl is understood as
meaning saturated and unsaturated (but not aromatic) cyclic
hydrocarbons (without a heteroatom in the ring), which can be
unsubstituted or once or several times substituted. Furthermore,
C.sub.3-4-cycloalkyl represents C3- or C4-cycloalkyl,
C.sub.3-5-cycloalkyl represents C3-, C4- or C5-cycloalkyl,
C.sub.3-6-cycloalkyl represents C3-, C4-, C5- or C6-cycloalkyl,
C.sub.3-7-cycloalkyl represents C3-, C4-, C5-, C6- or
C7-cycloalkyl, C.sub.3-8-cycloalkyl represents C3-, C4-, C5-, C6-,
C7- or C8-cycloalkyl, C.sub.4-5-cycloalkyl represents C4- or
C5-cycloalkyl, C.sub.4-6-cycloalkyl represents C4-, C5- or
C6-cycloalkyl, C.sub.4-7-cycloalkyl represents C4-, C5-, C6- or
C7-cycloalkyl, C.sub.5-6-cycloalkyl represents C5- or C6-cycloalkyl
and C.sub.5-7-cycloalkyl represents C5-, C6- or C7-cycloalkyl.
Examples are cyclopropyl, 2-methylcyclopropyl, cyclopropylmethyl,
cyclobutyl, cyclopentyl, cyclopentylmethyl, cyclohexyl,
cycloheptyl, cyclooctyl, and also adamantly. Preferably in the
context of this invention cycloalkyl is C.sub.3-8cycloalkyl like
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or
cyclooctyl; or is C.sub.3-7cycloalkyl like cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, or cycloheptyl; or is C.sub.3-6cycloalkyl
like cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, especially
cyclopentyl or cyclohexyl.
[0076] Aryl is understood as meaning 5 to 18 membered mono or
polycyclic ring systems with at least one aromatic ring but without
heteroatoms even in only one of the rings. Examples are phenyl,
naphthyl, fluoranthenyl, fluorenyl, tetralinyl or indanyl,
9H-fluorenyl or anthracenyl radicals, which can be unsubstituted or
once or several times substituted. Most preferably aryl is
understood in the context of this invention as phenyl, naphtyl or
anthracenyl, preferably is phenyl.
[0077] A heterocyclyl radical or group (also called heterocyclyl
hereinafter) is understood as meaning 5 to 18 membered mono or
polycyclic heterocyclic ring systems, with at least one saturated
or unsaturated ring which contains one or more heteroatoms from the
group consisting of nitrogen, oxygen and/or sulfur in the ring. A
heterocyclic group can also be substituted once or several
times.
[0078] Examples include non-aromatic heterocyclyls such as
tetrahydropyrane, oxazepane, morpholine, piperidine, pyrrolidine as
well as heteroaryls such as furan, benzofuran, thiophene,
benzothiophene, pyrrole, pyridine, pyrimidine, pyrazine, quinoline,
isoquinoline, phthalazine, thiazole, benzothiazole, indole,
benzotriazole, carbazole and quinazoline.
[0079] Subgroups inside the heterocyclyls as understood herein
include heteroaryls and non-aromatic heterocyclyls. [0080] the
heteroaryl (being equivalent to heteroaromatic radicals or aromatic
heterocyclyls) is an aromatic 5 to 18 membered mono or polycyclic
heterocyclic ring system of one or more rings of which at least one
aromatic ring contains one or more heteroatoms from the group
consisting of nitrogen, oxygen and/or sulfur in the ring;
preferably is an aromatic 5 to 18 membered mono or polycyclic
heterocyclic ring system of one or two rings of which at least one
aromatic ring contains one or more heteroatoms from the group
consisting of nitrogen, oxygen and/or sulfur in the ring, more
preferably is selected from furan, benzofuran, thiophene,
benzothiophene, pyrrole, pyridine, pyrimidine, pyrazine, quinoline,
isoquinoline, phthalazine, benzothiazole, indole, benzotriazole,
carbazole, quinazoline, thiazole, imidazole, pyrazole, oxazole,
thiophene and benzimidazole; [0081] the non-aromatic heterocyclyl
is a 5 to 18 membered mono or polycyclic heterocyclic ring system
of one or more rings of which at least one ring--with this (or
these) ring(s) then not being aromatic--contains one or more
heteroatoms from the group consisting of nitrogen, oxygen and/or
sulfur in the ring; preferably is a 5 to 18 membered mono or
polycyclic heterocyclic ring system of one or two rings of which
one or both rings--with this one or two rings then not being
aromatic--contain/s one or more heteroatoms from the group
consisting of nitrogen, oxygen and/or sulfur in the ring, more
preferably is selected from oxazepam, pyrrolidine, piperidine,
piperazine, tetrahydropyran, morpholine, indoline, oxopyrrolidine,
benzodioxane, oxetane, especially is benzodioxane, morpholine,
tetrahydropyran, piperidine, oxopyrrolidine, oxetane and
pyrrolidine.
[0082] Preferably in the context of this invention heterocyclyl is
defined as a 5 to 18 membered mono or polycyclic heterocyclic ring
system of one or more saturated or unsaturated rings of which at
least one ring contains one or more heteroatoms from the group
consisting of nitrogen, oxygen and/or sulfur in the ring.
Preferably it is a 5 to 18 membered mono or polycyclic heterocyclic
ring system of one or two saturated or unsaturated rings of which
at least one ring contains one or more heteroatoms from the group
consisting of nitrogen, oxygen and/or sulfur in the ring.
[0083] Preferred examples of heterocyclyls include oxetane,
oxazepan, pyrrolidine, imidazole, oxadiazole, tetrazole, pyridine,
pyrimidine, piperidine, piperazine, benzofuran, benzimidazole,
indazole, benzodiazole, thiazole, benzothiazole, tetrahydropyrane,
morpholine, indoline, furan, triazole, isoxazole, pyrazole,
thiophene, benzothiophene, pyrrole, pyrazine,
pyrrolo[2,3b]pyridine, quinoline, isoquinoline, phthalazine,
benzo-1,2,5-thiadiazole, indole, benzotriazole, benzoxazole
oxopyrrolidine, pyrimidine, benzodioxolane, benzodioxane, carbazole
and quinazoline, especially is pyridine, pyrazine, indazole,
benzodioxane, thiazole, benzothiazole, morpholine,
tetrahydropyrane, pyrazole, imidazole, piperidine, thiophene,
indole, benzimidazole, pyrrolo[2,3b]pyridine, benzoxazole,
oxopyrrolidine, pyrimidine, oxazepane, oxetane and pyrrolidine.
[0084] In the context of this invention oxopyrrolidine is
understood as meaning pyrrolidin-2-one.
[0085] In connection with aromatic heterocycyls (heteroaryls),
non-aromatic heterocyclyls, aryls and cycloalkyls, when a ring
system falls within two or more of the above cycle definitions
simultaneously, then the ring system is defined first as an
aromatic heterocyclyl (heteroaryl) if at least one aromatic ring
contains a heteroatom. If no aromatic ring contains a heteroatom,
then the ring system is defined as a non-aromatic heterocyclyl if
at least one non-aromatic ring contains a heteroatom. If no
non-aromatic ring contains a heteroatom, then the ring system is
defined as an aryl if it contains at least one aryl cycle. If no
aryl is present, then the ring system is defined as a cycloalkyl if
at least one non-aromatic cyclic hydrocarbon is present.
[0086] In the context of this invention alkylaryl is understood as
meaning an aryl group (see above) being connected to another atom
through a C.sub.1-6-alkyl (see above) which may be branched or
linear and is unsubstituted or substituted once or several times.
Preferably alkylaryl is understood as meaning an aryl group (see
above) being connected to another atom through 1 to 4
(--CH.sub.2--) groups. Most preferably alkylaryl is benzyl (i.e.
--CH.sub.2-phenyl).
[0087] In the context of this invention alkylheterocyclyl is
understood as meaning an heterocyclyl group being connected to
another atom through a C.sub.1-6-alkyl (see above) which may be
branched or linear and is unsubstituted or substituted once or
several times. Preferably alkylheterocyclyl is understood as
meaning an heterocyclyl group (see above) being connected to
another atom through 1 to 4 (--CH.sub.2--) groups. Most preferably
alkylheterocydyl is --CH.sub.2-pyridine.
[0088] In the context of this invention alkylcycloalkyl is
understood as meaning an cycloalkyl group being connected to
another atom through a C.sub.1-6-alkyl (see above) which may be
branched or linear and is unsubstituted or substituted once or
several times. Preferably alkylcycloalkyl is understood as meaning
an cycloalkyl group (see above) being connected to another atom
through 1 to 4 (--CH.sub.2--) groups. Most preferably
alkylcycloalkyl is --CH.sub.2-cyclopropyl.
[0089] Preferably, the aryl is a monocyclic aryl. More preferably
the aryl is a 5, 6 or 7 membered monocyclic aryl. Even more
preferably the aryl is a 5 or 6 membered monocyclic aryl.
[0090] Preferably, the heteroaryl is a monocyclic heteroaryl. More
preferably the heteroaryl is a 5, 6 or 7 membered monocyclic
heteroaryl. Even more preferably the heteroaryl is a 5 or 6
membered monocyclic heteroaryl.
[0091] Preferably, the non-aromatic heterocyclyl is a monocyclic
non-aromatic heterocycyl. More preferably the non-aromatic
heterocyclyl is a 4, 5, 6 or 7 membered monocyclic non-aromatic
heterocyclyl. Even more preferably the non-aromatic heterocyclyl is
a 5 or 6 membered monocyclic non-aromatic heterocyclyl.
[0092] Preferably, the cycloalkyl is a monocyclic cycloalkyl. More
preferably the cycloalkyl is a 3, 4, 5, 6, 7 or 8 membered
monocyclic cycloalkyl. Even more preferably the cycloalkyl is a 3,
4, 5 or 6 membered monocyclic cycloalkyl.
[0093] In connection with aryl (including alkyl-aryl), cycloalkyl
(including alkyl-cycloalkyl), or heterocyclyl (including
alkyl-heterocyclyl), substituted is understood--unless defined
otherwise--as meaning substitution of the ring-system of the aryl
or alkyl-aryl, cycloalkyl or alkyl-cycloalkyl; heterocycyl or
alkyl-heterocyclyl with one or more of halogen (F, Cl, Br, I),
--R.sub.c, --OR.sub.c, --CN, --NO.sub.2, --NR.sub.cR.sub.c''',
--C(O)OR.sub.c, NR.sub.cC(O)R.sub.c', --C(O)NR.sub.cR.sub.c',
--NR.sub.cS(O).sub.2R.sub.c', .dbd.O, --OCH.sub.2CH.sub.2OH,
--NR.sub.cC(O)NR.sub.c'R.sub.c'', --S(O).sub.2NR.sub.cR.sub.c',
--NR.sub.cS(O).sub.2NR.sub.c'R.sub.c'', haloalkyl, haloalkoxy,
--SR.sub.c, --S(O)R.sub.c, --S(O).sub.2R.sub.c or
C(CH.sub.3)OR.sub.c; NR.sub.cR.sub.c''', with R.sub.c, R.sub.c',
R.sub.c'', and R.sub.c''' independently being either H or a
saturated or unsaturated, linear or branched, substituted or
unsubstituted C.sub.1-6-alkyl; a saturated or unsaturated, linear
or branched, substituted or unsubstituted C.sub.1-6-alkyl; a
saturated or unsaturated, linear or branched, substituted or
unsubstituted --O--C.sub.1-6-alkyl (alkoxy); a saturated or
unsaturated, linear or branched, substituted or unsubstituted
--S--C.sub.1-6-alkyl; a saturated or unsaturated, linear or
branched, substituted or unsubstituted
--C(O)--C.sub.1-6-alkyl-group; a saturated or unsaturated, linear
or branched, substituted or unsubstituted
--C(O)--O--C.sub.1-6-alkyl-group; a substituted or unsubstituted
aryl or alkyl-aryl; a substituted or unsubstituted cycloalkyl or
alkyl-cycloalkyl; a substituted or unsubstituted heterocyclyl or
alkyl-heterocyclyl, being R.sub.c one of R.sub.11, R.sub.12 or
R.sub.14, (being R.sub.c' one of R.sub.11', R.sub.12' or R.sub.14';
being R.sub.c'' one of R.sub.11'', R.sub.12'' or R.sub.14'': being
R.sub.c''' one of R.sub.11''', R.sub.12''' or R.sub.14'''; being
R.sub.c'''' one of R.sub.11'''', R.sub.12'''' or R.sub.14''''),
wherein R.sub.1 to R.sub.14'''' and R.sub.x and R.sub.x' are as
defined in the description, and wherein when different radicals
R.sub.1 to R.sub.14'''' and R.sub.x and R.sub.x' are present
simultaneously in Formula I they may be identical or different.
[0094] Most preferably in connection with aryl (including
alkyl-aryl), cycloalkyl (including alkyl-cycloalkyl), or
heterocyclyl (including alkyl-heterocyclyl), substituted is
understood in the context of this invention that any aryl,
cycloalkyl and heterocyclyl which is substituted is substituted
(also in an alyklaryl, alkylcycloalkyl or alkylheterocyclyl) with
one or more of halogen (F, Cl, Br, I), --R.sub.c, --OR.sub.c, --CN,
--NO.sub.2, --NR.sub.cR.sub.c''', NR.sub.cC(O)R.sub.c',
--NR.sub.cS(O).sub.2R.sub.c', .dbd.O, haloalkyl, haloalkoxy, or
C(CH.sub.3)OR.sub.c; --OC.sub.1-4alkyl being unsubstituted or
substituted with one or more of OR.sub.c or halogen (F, Cl, I, Br),
--CN, or --C.sub.1-4alkyl being unsubstituted or substituted with
one or more of OR.sub.c or halogen (F, Cl, I, Br), being R.sub.c
one of R.sub.11, R.sub.12 or R.sub.14, (being R.sub.c' one of
R.sub.11', R.sub.12' or R.sub.14'; being R.sub.c'' one of
R.sub.11'', R.sub.12'' or R.sub.14''; being R.sub.c''' one of
R.sub.11''', R.sub.12''', or R.sub.14'''; being R.sub.c'''' one of
R.sub.11'''', R.sub.12'''', or R.sub.14''''), wherein R.sub.1 to
R.sub.14'''' and R.sub.x and R.sub.x' are as defined in the
description, and wherein when different radicals R.sub.1 to
R.sub.14'''' and R.sub.x and R.sub.x' are present simultaneously in
Formula I they may be identical or different.
[0095] Additionally to the above-mentioned substitutions, in
connection with cycloalkyl (including alkyl-cycloalkyl), or
heterocycly (including alkylheterocyclyl) namely non-aromatic
heterocyclyl (including non-aromatic alkyl-heterocyclyl),
substituted is also understood--unless defined otherwise--as
meaning substitution of the ring-system of the cycloalkyl or
alkyl-cycloalkyl; non-aromatic heterocyclyl or non aromatic
alkyl-heterocycyl with or
##STR00024##
.dbd.O.
[0096] In connection with cycloalkyl (including alkyl-cycloalkyl),
or heterocycly (including alkylheterocyclyl) namely non-aromatic
heterocyclyl (including non-aromatic alkyl-heterocyclyl),
substituted is also understood--unless defined otherwise--as
meaning substitution of the ring-system of the cycloalkyl or
alkyl-cycloalkyl; non-aromatic heterocyclyl or non aromatic
alkyl-heterocyclyl with
##STR00025##
leading to a spiro structure) or with .dbd.O.
[0097] A ring system is a system consisting of at least one ring of
connected atoms but including also systems in which two or more
rings of connected atoms are joined with "joined" meaning that the
respective rings are sharing one (like a spiro structure), two or
more atoms being a member or members of both joined rings.
[0098] The term "leaving group" means a molecular fragment that
departs with a pair of electrons in heterolytic bond cleavage.
Leaving groups can be anions or neutral molecules. Common anionic
leaving groups are halides such as Cl--, Br--, and I--, and
sulfonate esters, such as tosylate (TsO--) or mesylate.
[0099] The term "salt" is to be understood as meaning any form of
the active compound used according to the invention in which it
assumes an ionic form or is charged and is coupled with a
counter-ion (a cation or anion) or is in solution. By this are also
to be understood complexes of the active compound with other
molecules and ions, in particular complexes via ionic
interactions.
[0100] The term "physiologically acceptable salt" means in the
context of this invention any salt that is physiologically
tolerated (most of the time meaning not being toxic--especially not
caused by the counter-ion) if used appropriately for a treatment
especially if used on or applied to humans and/or mammals.
[0101] These physiologically acceptable salts can be formed with
cations or bases and in the context of this invention is understood
as meaning salts of at least one of the compounds used according to
the invention--usually a (deprotonated) acid--as an anion with at
least one, preferably inorganic, cation which is physiologically
tolerated--especially if used on humans and/or mammals. The salts
of the alkali metals and alkaline earth metals are particularly
preferred, and also those with NH.sub.4, but in particular (mono)-
or (di)sodium, (mono)- or (di)potassium, magnesium or calcium
salts.
[0102] Physiologically acceptable salts can also be formed with
anions or acids and in the context of this invention is understood
as meaning salts of at least one of the compounds used according to
the invention as the cation with at least one anion which are
physiologically tolerated--especially if used on humans and/or
mammals. By this is understood in particular, in the context of
this invention, the salt formed with a physiologically tolerated
acid, that is to say salts of the particular active compound with
inorganic or organic acids which are physiologically
tolerated--especially if used on humans and/or mammals. Examples of
physiologically tolerated salts of particular acids are salts of:
hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic
acid, formic acid, acetic acid, oxalic acid, succinic acid, malic
acid, tartaric acid, mandelic acid, fumaric acid, lactic acid or
citric acid.
[0103] The compounds of the invention may be present in crystalline
form or in the form of free compounds like a free base or acid.
[0104] Any compound that is a solvate of a compound according to
the invention like a compound according to general formula I
defined above is understood to be also covered by the scope of the
invention. Methods of solvation are generally known within the art.
Suitable solvates are pharmaceutically acceptable solvates. The
term "solvate" according to this invention is to be understood as
meaning any form of the active compound according to the invention
in which this compound has attached to it via non-covalent binding
another molecule (most likely a polar solvent). Especially
preferred examples include hydrates and alcoholates, like
methanolates or ethanolates.
[0105] Any compound that is a prodrug of a compound according to
the invention like a compound according to general formula I
defined above is understood to be also covered by the scope of the
invention. The term "prodrug" is used in its broadest sense and
encompasses those derivatives that are converted in vivo to the
compounds of the invention. Such derivatives would readily occur to
those skilled in the art, and include, depending on the functional
groups present in the molecule and without limitation, the
following derivatives of the present compounds: esters, amino acid
esters, phosphate esters, metal salts sulfonate esters, carbamates,
and amides. Examples of well known methods of producing a prodrug
of a given acting compound are known to those skilled in the art
and can be found e.g. in Krogsgaard-Larsen et al. "Textbook of Drug
design and Discovery" Taylor & Francis (April 2002).
[0106] Any compound that is a N-oxide of a compound according to
the invention like a compound according to general formula I
defined above is understood to be also covered by the scope of the
invention.
[0107] Unless otherwise stated, the compounds of the invention are
also meant to include compounds which differ only in the presence
of one or more isotopically enriched atoms. For example, compounds
having the present structures except for the replacement of a
hydrogen by a deuterium or tritium, or the replacement of a carbon
by .sup.13C- or .sup.14C-enriched carbon or of a nitrogen by
.sup.15N-enriched nitrogen are within the scope of this
invention.
[0108] The compounds of formula (I) as well as their salts or
solvates of the compounds are preferably in pharmaceutically
acceptable or substantially pure form. By pharmaceutically
acceptable form is meant, inter alia, having a pharmaceutically
acceptable level of purity excluding normal pharmaceutical
additives such as diluents and carriers, and including no material
considered toxic at normal dosage levels. Purity levels for the
drug substance are preferably above 50%, more preferably above 70%,
most preferably above 90%. In a preferred embodiment it is above
95% of the compound of formula (I), or of its salts. This applies
also to its solvates or prodrugs.
[0109] In a further embodiment the compound according to the
invention of general Formula (I)
##STR00026##
is a compound wherein R.sub.1 is
##STR00027##
m is 1, 2, 3, 4 or 5; n is 0, 1, 2, 3, 4 or 5; p is 0 or 1; q is 0,
1 or 2; r is 0, 1 or 2; X is a bond, --C(R.sub.xR.sub.x')--,
--C(O)--, --O--, --C(O)NR.sub.7--, --NR.sub.7C(O)-- or --C(O)O--;
[0110] wherein R.sub.x is selected from halogen or substituted or
unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted
C.sub.2-6 alkenyl substituted or unsubstituted C.sub.2-6 alkynyl,
and --OR.sub.7; [0111] R.sub.x' is selected from hydrogen, halogen
or substituted or unsubstituted C.sub.1-6 alkyl, substituted or
unsubstituted C.sub.2-6 alkenyl and substituted or unsubstituted
C.sub.2-6 alkynyl; [0112] R.sub.7 is selected from hydrogen,
substituted or unsubstituted C.sub.1-6 alkyl, substituted or
unsubstituted C.sub.2-6 alkenyl and substituted or unsubstituted
C.sub.2-6 alkynyl;
Y is --CH.sub.2-- or --C(O)--;
[0113] R.sub.1' is selected from substituted or unsubstituted
C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl,
substituted or unsubstituted C.sub.2-6 alkynyl, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted aryl and
substituted or unsubstituted heterocyclyl; [0114] wherein said
cycloalkyl, aryl or heterocyclyl in R.sub.1' if substituted, is
substituted with one or more substituent/s selected from halogen,
--R.sub.11, --OR.sub.11, --NO.sub.2, --NR.sub.11R.sub.11''',
NR.sub.11C(O)R.sub.11', --NR.sub.11S(O).sub.2R.sub.11',
--S(O).sub.2NR.sub.11R.sub.11',
--NR.sub.11C(O)NR.sub.11'R.sub.11'', --SR.sub.11, --S(O)R.sub.11,
S(O).sub.2R.sub.11, --CN, haloalkyl, haloalkoxy, --C(O)OR.sub.11,
--C(O)NR.sub.11R.sub.11', --OCH.sub.2CH.sub.2OH,
--NR.sub.11S(O).sub.2NR.sub.22'R.sub.11'' and
C(CH.sub.3).sub.2OR.sub.11; [0115] additionally, the cycloalkyl or
non-aromatic heterocyclyl in R.sub.1', if substituted, may also be
substituted with
##STR00028##
[0115] or .dbd.O;
[0116] wherein the alkyl, alkenyl or alkynyl in R.sub.1', if
substituted, is substituted with one or more substituent/s selected
from --OR.sub.11, halogen, --CN, haloalkyl, haloalkoxy and
--NR.sub.11R.sub.11'''; [0117] wherein R.sub.11, R.sub.11' and
R.sub.11'' are independently selected from hydrogen, unsubstituted
C.sub.1-6 alkyl, unsubstituted C.sub.2-6 alkenyl and unsubstituted
C.sub.2-6 alkynyl; [0118] and wherein R.sub.11''' is selected from
hydrogen, unsubstituted C.sub.1-6 alkyl, unsubstituted C.sub.2-6
alkenyl, unsubstituted C.sub.2-6 alkynyl and -Boc; R.sub.2 is
selected from hydrogen, substituted or unsubstituted C.sub.1-6
alkyl, substituted or unsubstituted C.sub.2-6 alkenyl, substituted
or unsubstituted C.sub.2-6 alkynyl, substituted or unsubstituted
cycloalkyl, substituted or unsubstituted aryl and substituted or
unsubstituted heterocyclyl, [0119] wherein said cycloalkyl, aryl or
heterocyclyl in R.sub.2, if substituted, is substituted with one or
more substituent/s selected from halogen, --R.sub.12, --OR.sub.12,
--NO.sub.2, --NR.sub.12R.sub.12''', NR.sub.12C(O)R.sub.12',
--NR.sub.12S(O).sub.2R.sub.12', --S(O).sub.2NR.sub.12R.sub.12',
--NR.sub.12C(O)NR.sub.12'R.sub.12'', --SR.sub.12, --S(O)R.sub.12,
S(O).sub.2R.sub.12, --CN, haloalkyl, haloalkoxy, --C(O)OR.sub.12,
--C(O)NR.sub.12R.sub.12', --OCH.sub.2CH.sub.2OH,
--NR.sub.12S(O).sub.2NR.sub.12'R.sub.12'' and
C(CH.sub.3).sub.2OR.sub.12; [0120] additionally, the cycloalkyl or
non-aromatic heterocyclyl in R.sub.2, if substituted, may also be
substituted with
##STR00029##
[0120] or .dbd.O;
[0121] wherein the alkyl, alkenyl or alkynyl in R.sub.2, if
substituted, is substituted with one or more substituent/s selected
from --OR.sub.12, halogen, --CN, haloalkyl, haloalkoxy and
--NR.sub.12R.sub.12'''; [0122] wherein R.sub.12, R.sub.12' and
R.sub.12'' are independently selected from hydrogen, unsubstituted
C.sub.1-6 alkyl, unsubstituted C.sub.2-6 alkenyl and unsubstituted
C.sub.2-6 alkynyl; [0123] and wherein R.sub.12''' is selected from
hydrogen, unsubstituted C.sub.1-6 alkyl, unsubstituted C.sub.2-6
alkenyl, unsubstituted C.sub.2-6 alkynyl and -Boc; R.sub.a is
selected from substituted or unsubstituted C.sub.1-6 alkyl,
substituted or unsubstituted C.sub.2-6 alkenyl and substituted or
unsubstituted C.sub.2-6 alkynyl; R.sub.3' is selected from
hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted
or unsubstituted C.sub.2-6 alkenyl and substituted or unsubstituted
C.sub.2-6 alkynyl; alternatively, R.sub.3 and R.sub.3' may form
together with the carbon atom to which they are attached a
substituted or unsubstituted cycloalkyl; R.sub.4 and R.sub.4' are
independently selected from hydrogen, substituted or unsubstituted
C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl,
substituted or unsubstituted C.sub.2-6 alkynyl, --CHOR.sub.9 and
--C(O)OR.sub.9; [0124] wherein R.sub.9 is selected from hydrogen,
substituted or unsubstituted C.sub.1-9 alkyl, substituted or
unsubstituted C.sub.2-9 alkenyl and substituted or unsubstituted
C.sub.2-9 alkynyl; R.sub.5 and R.sub.5' are independently selected
from hydrogen, substituted or unsubstituted C.sub.1-6 alkyl,
substituted or unsubstituted C.sub.2-6 alkenyl, substituted or
unsubstituted C.sub.2-6 alkynyl, substituted or unsubstituted
cycloalkyl, substituted or unsubstituted aryl, substituted or
unsubstituted heterocyclyl, --CHOR.sub.8 and --C(O)OR.sub.8; [0125]
wherein R.sub.8 is selected from hydrogen, substituted or
unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted
C.sub.2-6 alkenyl and substituted or unsubstituted C.sub.2-6
alkynyl; alternatively R.sub.5 and R.sub.5' taken together with the
connecting C-atom may form a substituted or unsubstituted
cycloalkyl or a substituted or unsubstituted heterocyclyl; R.sub.6
and R.sub.6' are independently selected from hydrogen, substituted
or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted
C.sub.2-6 alkenyl, substituted or unsubstituted C.sub.2-6 alkynyl,
--CHOR.sub.10 and --C(O)OR.sub.10; [0126] wherein R.sub.10 is
selected from hydrogen, substituted or unsubstituted C.sub.1-6
alkyl, substituted or unsubstituted C.sub.2-6 alkenyl and
substituted or unsubstituted C.sub.2-6 alkynyl; the alkyl, alkenyl
or alkynyl, other than those defined in R.sub.1' or R.sub.2, if
substituted, is substituted with one or more substituent/s selected
from --OR.sub.13, halogen, --CN, haloalkyl, haloalkoxy and
--NR.sub.13R.sub.13'''; [0127] wherein R.sub.13, are independently
selected from hydrogen, unsubstituted C.sub.1-6 alkyl,
unsubstituted C.sub.2-6 alkenyl, and unsubstituted C.sub.2-6
alkynyl; [0128] R.sub.13''' is selected from hydrogen,
unsubstituted C.sub.1-6 alkyl, unsubstituted C.sub.2-6 alkenyl,
unsubstituted C.sub.2-6 alkynyl and -Boc; the aryl, heterocyclyl or
cycloalkyl other than those defined in R.sub.1' or R.sub.2, if
substituted, is substituted with one or more substituent/s selected
from halogen, --R.sub.14, --OR.sub.14, --NO.sub.2,
--NR.sub.14R.sub.14''', NR.sub.14C(O)R.sub.14',
--NR.sub.14S(O).sub.2R.sub.14', --S(O).sub.2NR.sub.14R.sub.14',
--NR.sub.14C(O)NR.sub.14'R.sub.14'', --SR.sub.14, --S(O)R.sub.14,
S(O).sub.2R.sub.14, --CN, haloalkyl, haloalkoxy, --C(O)OR.sub.14,
--C(O)NR.sub.14R.sub.14, --OCH.sub.2CH.sub.2OH,
--NR.sub.14S(O).sub.2NR.sub.14'R.sub.14'' and
C(CH.sub.3).sub.2OR.sub.14; additionally, wherein cycloalkyl or
non-aromatic heterocyclyl, other than those defined in R.sub.1', or
R.sub.2, if substituted, may also be substituted with
##STR00030##
[0128] or .dbd.O;
[0129] wherein R.sub.14, R.sub.14' and R.sub.14'' are independently
selected from hydrogen, unsubstituted C.sub.1-6 alkyl,
unsubstituted C.sub.2-6 alkenyl, unsubstituted C.sub.2-6 alkynyl,
unsubstituted aryl, unsubstituted cycloalkyl and unsubstituted
heterocyclyl; [0130] and wherein R.sub.14''' is selected from
hydrogen, unsubstituted C.sub.1-6 alkyl, unsubstituted C.sub.2-6
alkenyl, unsubstituted C.sub.2-6 alkynyl and -Boc;
[0131] These preferred compounds according to the invention are
optionally in form of one of the stereoisomers, preferably
enantiomers or diastereomers, a racemate or in form of a mixture of
at least two of the stereoisomers, preferably enantiomers and/or
diastereomers, in any mixing ratio, or a corresponding salt
thereof, or a corresponding solvate thereof.
[0132] In a further embodiment the compound according to the
invention of general Formula (I) is a compound wherein
m is 1, 2, 3, 4 or 5; optionally in form of one of the
stereoisomers, preferably enantiomers or diastereomers, a racemate
or in form of a mixture of at least two of the stereoisomers,
preferably enantiomers and/or diastereomers, in any mixing ratio,
or a corresponding salt thereof, or a corresponding solvate
thereof.
[0133] In a further embodiment the compound according to the
invention of general Formula (I) is a compound wherein
n is 0, 1, 2, 3, 4 or 5; optionally in form of one of the
stereoisomers, preferably enantiomers or diastereomers, a racemate
or in form of a mixture of at least two of the stereoisomers,
preferably enantiomers and/or diastereomers, in any mixing ratio,
or a corresponding salt thereof, or a corresponding solvate
thereof.
[0134] In a further embodiment the compound according to the
invention of general f Formula (I) is a compound wherein
p is 0 or 1; optionally in form of one of the stereoisomers,
preferably enantiomers or diastereomers, a racemate or in form of a
mixture of at least two of the stereoisomers, preferably
enantiomers and/or diastereomers, in any mixing ratio, or a
corresponding salt thereof, or a corresponding solvate thereof.
[0135] In a further embodiment the compound according to the
invention of general f Formula (I) is a compound wherein
q is 0, 1 or 2; optionally in form of one of the stereoisomers,
preferably enantiomers or diastereomers, a racemate or in form of a
mixture of at least two of the stereoisomers, preferably
enantiomers and/or diastereomers, in any mixing ratio, or a
corresponding salt thereof, or a corresponding solvate thereof.
[0136] In a further embodiment the compound according to the
invention of general f Formula (I) is a compound wherein
r is 0, 1 or 2; optionally in form of one of the stereoisomers,
preferably enantiomers or diastereomers, a racemate or in form of a
mixture of at least two of the stereoisomers, preferably
enantiomers and/or diastereomers, in any mixing ratio, or a
corresponding salt thereof, or a corresponding solvate thereof.
[0137] In a further embodiment the compound according to the
invention of general Formula (I) is a compound wherein
X is a bond, --C(R.sub.xR.sub.x')--, --C(O)--, --O--,
--C(O)NR.sub.7--, --NR.sub.7C(O)-- or --C(O)O--; optionally in form
of one of the stereoisomers, preferably enantiomers or
diastereomers, a racemate or in form of a mixture of at least two
of the stereoisomers, preferably enantiomers and/or diastereomers,
in any mixing ratio, or a corresponding salt thereof, or a
corresponding solvate thereof.
[0138] In another preferred embodiment of the compound according to
the invention of general Formula (I) is a compound wherein
X is a bond; optionally in form of one of the stereoisomers,
preferably enantiomers or diastereomers, a racemate or in form of a
mixture of at least two of the stereoisomers, preferably
enantiomers and/or diastereomers, in any mixing ratio, or a
corresponding salt thereof, or a corresponding solvate thereof.
[0139] In another preferred embodiment of the compound according to
the invention of general Formula (I) is a compound wherein
X is --C(R.sub.xR.sub.x')--; optionally in form of one of the
stereoisomers, preferably enantiomers or diastereomers, a racemate
or in form of a mixture of at least two of the stereoisomers,
preferably enantiomers and/or diastereomers, in any mixing ratio,
or a corresponding salt thereof, or a corresponding solvate
thereof.
[0140] In another preferred embodiment of the compound according to
the invention of general Formula (I) is a compound wherein
X is --O--;
[0141] optionally in form of one of the stereoisomers, preferably
enantiomers or diastereomers, a racemate or in form of a mixture of
at least two of the stereoisomers, preferably enantiomers and/or
diastereomers, in any mixing ratio, or a corresponding salt
thereof, or a corresponding solvate thereof.
[0142] In another preferred embodiment of the compound according to
the invention of general Formula (I) is a compound wherein
X is C.dbd.O;
[0143] optionally in form of one of the stereoisomers, preferably
enantiomers or diastereomers, a racemate or in form of a mixture of
at least two of the stereoisomers, preferably enantiomers and/or
diastereomers, in any mixing ratio, or a corresponding salt
thereof, or a corresponding solvate thereof.
[0144] In another preferred embodiment of the compound according to
the invention of general Formula (I) is a compound wherein
X is --C(O)NR.sub.7--;
[0145] optionally in form of one of the stereoisomers, preferably
enantiomers or diastereomers, a racemate or in form of a mixture of
at least two of the stereoisomers, preferably enantiomers and/or
diastereomers, in any mixing ratio, or a corresponding salt
thereof, or a corresponding solvate thereof.
[0146] In another preferred embodiment of the compound according to
the invention of general Formula (I) is a compound wherein
X is --NR.sub.7C(O)--;
[0147] optionally in form of one of the stereoisomers, preferably
enantiomers or diastereomers, a racemate or in form of a mixture of
at least two of the stereoisomers, preferably enantiomers and/or
diastereomers, in any mixing ratio, or a corresponding salt
thereof, or a corresponding solvate thereof.
[0148] In another preferred embodiment of the compound according to
the invention of general Formula (I) is a compound wherein
X is --C(O)O--;
[0149] optionally in form of one of the stereoisomers, preferably
enantiomers or diastereomers, a racemate or in form of a mixture of
at least two of the stereoisomers, preferably enantiomers and/or
diastereomers, in any mixing ratio, or a corresponding salt
thereof, or a corresponding solvate thereof.
[0150] In a further embodiment the compound according to the
invention of general Formula (I) is a compound wherein
Y is --CH.sub.2-- or --C(O)--;
[0151] optionally in form of one of the stereoisomers, preferably
enantiomers or diastereomers, a racemate or in form of a mixture of
at least two of the stereoisomers, preferably enantiomers and/or
diastereomers, in any mixing ratio, or a corresponding salt
thereof, or a corresponding solvate thereof.
[0152] In a further embodiment the compound according to the
invention of general Formula (I) is a compound wherein
Y is --CH.sub.2--;
[0153] optionally in form of one of the stereoisomers, preferably
enantiomers or diastereomers, a racemate or in form of a mixture of
at least two of the stereoisomers, preferably enantiomers and/or
diastereomers, in any mixing ratio, or a corresponding salt
thereof, or a corresponding solvate thereof.
[0154] In a further embodiment the compound according to the
invention of general Formula (I) is a compound wherein
Y is --C(O)--;
[0155] optionally in form of one of the stereoisomers, preferably
enantiomers or diastereomers, a racemate or in form of a mixture of
at least two of the stereoisomers, preferably enantiomers and/or
diastereomers, in any mixing ratio, or a corresponding salt
thereof, or a corresponding solvate thereof.
[0156] In another preferred embodiment of the compound according to
the invention of general Formula (I) is a compound wherein
R.sub.1 is
##STR00031##
[0157] optionally in form of one of the stereoisomers, preferably
enantiomers or diastereomers, a racemate or in form of a mixture of
at least two of the stereoisomers, preferably enantiomers and/or
diastereomers, in any mixing ratio, or a corresponding salt
thereof, or a corresponding solvate thereof.
[0158] In another preferred embodiment of the compound according to
the invention of general Formula (I) is a compound wherein
R.sub.1 is
##STR00032##
[0159] optionally in form of one of the stereoisomers, preferably
enantiomers or diastereomers, a racemate or in form of a mixture of
at least two of the stereoisomers, preferably enantiomers and/or
diastereomers, in any mixing ratio, or a corresponding salt
thereof, or a corresponding solvate thereof.
[0160] In another preferred embodiment of the compound according to
the invention of general Formula (I) is a compound wherein
R.sub.1 is
##STR00033##
[0161] optionally in form of one of the stereoisomers, preferably
enantiomers or diastereomers, a racemate or in form of a mixture of
at least two of the stereoisomers, preferably enantiomers and/or
diastereomers, in any mixing ratio, or a corresponding salt
thereof, or a corresponding solvate thereof.
[0162] In a further embodiment the compound according to the
invention of general Formula (I) is a compound wherein
R.sub.1' is selected from substituted or unsubstituted C.sub.1-6
alkyl, substituted or unsubstituted C.sub.2-6 alkenyl, substituted
or unsubstituted C.sub.2-6 alkynyl, substituted or unsubstituted
cycloalkyl, substituted or unsubstituted aryl and substituted or
unsubstituted heterocyclyl; optionally in form of one of the
stereoisomers, preferably enantiomers or diastereomers, a racemate
or in form of a mixture of at least two of the stereoisomers,
preferably enantiomers and/or diastereomers, in any mixing ratio,
or a corresponding salt thereof, or a corresponding solvate
thereof.
[0163] In a further embodiment the compound according to the
invention of general Formula (I) is a compound wherein
R.sub.1' is selected from substituted or unsubstituted C.sub.1-6
alkyl, substituted or unsubstituted C.sub.2-6 alkenyl, substituted
or unsubstituted C.sub.2-6 alkynyl and substituted or unsubstituted
aryl; optionally in form of one of the stereoisomers, preferably
enantiomers or diastereomers, a racemate or in form of a mixture of
at least two of the stereoisomers, preferably enantiomers and/or
diastereomers, in any mixing ratio, or a corresponding salt
thereof, or a corresponding solvate thereof.
[0164] In a further embodiment the compound according to the
invention of general Formula (I) is a compound wherein
R.sub.1' is selected from substituted or unsubstituted C.sub.1-6
alkyl and substituted or unsubstituted aryl; optionally in form of
one of the stereoisomers, preferably enantiomers or diastereomers,
a racemate or in form of a mixture of at least two of the
stereoisomers, preferably enantiomers and/or diastereomers, in any
mixing ratio, or a corresponding salt thereof, or a corresponding
solvate thereof.
[0165] In a further embodiment the compound according to the
invention of general Formula (I) is a compound wherein
R.sub.2 is selected from hydrogen, substituted or unsubstituted
C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl,
substituted or unsubstituted C.sub.2-6 alkynyl, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted aryl and
substituted or unsubstituted heterocyclyl, optionally in form of
one of the stereoisomers, preferably enantiomers or diastereomers,
a racemate or in form of a mixture of at least two of the
stereoisomers, preferably enantiomers and/or diastereomers, in any
mixing ratio, or a corresponding salt thereof, or a corresponding
solvate thereof.
[0166] In a further embodiment the compound according to the
invention of general Formula (I) is a compound wherein
R.sub.2 is selected from substituted or unsubstituted C.sub.1-6
alkyl, substituted or unsubstituted C.sub.2-6 alkenyl, substituted
or unsubstituted C.sub.2-6 alkynyl and substituted or unsubstituted
aryl, optionally in form of one of the stereoisomers, preferably
enantiomers or diastereomers, a racemate or in form of a mixture of
at least two of the stereoisomers, preferably enantiomers and/or
diastereomers, in any mixing ratio, or a corresponding salt
thereof, or a corresponding solvate thereof.
[0167] In a further embodiment the compound according to the
invention of general Formula (I) is a compound wherein
R.sub.2 is selected from substituted or unsubstituted C.sub.1-6
alkyl and substituted or unsubstituted aryl, optionally in form of
one of the stereoisomers, preferably enantiomers or diastereomers,
a racemate or in form of a mixture of at least two of the
stereoisomers, preferably enantiomers and/or diastereomers, in any
mixing ratio, or a corresponding salt thereof, or a corresponding
solvate thereof.
[0168] In a further embodiment the compound according to the
invention of general Formula (I') is a compound wherein
R.sub.2 is selected from substituted or unsubstituted C.sub.1-6
alkyl and substituted or unsubstituted aryl.
[0169] In a further embodiment the compound according to the
invention of general Formula (I') is a compound wherein
R.sub.2 is selected from substituted or unsubstituted C.sub.1-6
alkyl and substituted or unsubstituted aryl and R.sub.5 and
R.sub.5' are both hydrogen.
[0170] In another further embodiment the compound according to the
invention of general Formula (I') is a compound wherein
R.sub.2 is selected from substituted or unsubstituted C.sub.1-6
alkyl and substituted or unsubstituted aryl, R.sub.5 and R.sub.5'
are both hydrogen and X is a bond or --O--.
[0171] In another further embodiment the compound according to the
invention of general Formula (I') is a compound wherein
R.sub.2 is selected from substituted or unsubstituted C.sub.1-6
alkyl and substituted or unsubstituted aryl, R.sub.5 and R.sub.5'
are both hydrogen and X is a bond or --O--, while R.sub.1, R.sub.3,
R.sub.3', Y, m, q and r are as defined in the description
above.
[0172] In another further embodiment the compound according to the
invention of general Formula (I') is a compound wherein
R.sub.2 is selected from substituted or unsubstituted C.sub.1-6
alkyl and substituted or unsubstituted aryl, R.sub.5 and R.sub.5'
are both hydrogen and X is a bond, while R.sub.1, R.sub.3,
R.sub.3', Y, m, q and r are as defined in the description
above.
[0173] In another preferred embodiment of the compound according to
the according to the invention of general Formula (I) is a compound
wherein
R.sub.3 is selected from substituted or unsubstituted C.sub.1-6
alkyl, substituted or unsubstituted C.sub.2-6 alkenyl and
substituted or unsubstituted C.sub.2-6 alkynyl; optionally in form
of one of the stereoisomers, preferably enantiomers or
diastereomers, a racemate or in form of a mixture of at least two
of the stereoisomers, preferably enantiomers and/or diastereomers,
in any mixing ratio, or a corresponding salt thereof, or a
corresponding solvate thereof.
[0174] In another preferred embodiment of the compound according to
the according to the invention of general Formula (I) is a compound
wherein
R.sub.3' is selected from hydrogen, substituted or unsubstituted
C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl and
substituted or unsubstituted C.sub.2-6 alkynyl; optionally in form
of one of the stereoisomers, preferably enantiomers or
diastereomers, a racemate or in form of a mixture of at least two
of the stereoisomers, preferably enantiomers and/or diastereomers,
in any mixing ratio, or a corresponding salt thereof, or a
corresponding solvate thereof.
[0175] In another preferred embodiment of the compound according to
the according to the invention of general Formula (I) is a compound
wherein
R.sub.3 and R.sub.3' may form together with the carbon atom to
which they are attached a substituted or unsubstituted cycloalkyl;
optionally in form of one of the stereoisomers, preferably
enantiomers or diastereomers, a racemate or in form of a mixture of
at least two of the stereoisomers, preferably enantiomers and/or
diastereomers, in any mixing ratio, or a corresponding salt
thereof, or a corresponding solvate thereof.
[0176] In another preferred embodiment of the compound according to
the invention of general Formula (I) is a compound wherein
R.sub.4 and R.sub.4' are independently selected from hydrogen,
substituted or unsubstituted C.sub.1-6 alkyl, substituted or
unsubstituted C.sub.2-6 alkenyl, substituted or unsubstituted
C.sub.2-6 alkynyl, --CHOR.sub.9 and --C(O)OR.sub.9; optionally in
form of one of the stereoisomers, preferably enantiomers or
diastereomers, a racemate or in form of a mixture of at least two
of the stereoisomers, preferably enantiomers and/or diastereomers,
in any mixing ratio, or a corresponding salt thereof, or a
corresponding solvate thereof.
[0177] In another preferred embodiment of the compound according to
the invention of general Formula (I) is a compound wherein
R.sub.5 and R.sub.5' are independently selected from hydrogen,
substituted or unsubstituted C.sub.1-6 alkyl, substituted or
unsubstituted C.sub.2-6 alkenyl, substituted or unsubstituted
C.sub.2-6 alkynyl, substituted or unsubstituted cycloalkyl,
substituted or unsubstituted aryl, substituted or unsubstituted
heterocyclyl, --CHOR.sub.8 and --C(O)OR.sub.8; optionally in form
of one of the stereoisomers, preferably enantiomers or
diastereomers, a racemate or in form of a mixture of at least two
of the stereoisomers, preferably enantiomers and/or diastereomers,
in any mixing ratio, or a corresponding salt thereof, or a
corresponding solvate thereof.
[0178] In another preferred embodiment of the compound according to
the invention of general Formula (I) is a compound wherein
R.sub.5 and R.sub.5' taken together with the connecting C-atom may
form a substituted or unsubstituted cycloalkyl or a substituted or
unsubstituted heterocycyl; optionally in form of one of the
stereoisomers, preferably enantiomers or diastereomers, a racemate
or in form of a mixture of at least two of the stereoisomers,
preferably enantiomers and/or diastereomers, in any mixing ratio,
or a corresponding salt thereof, or a corresponding solvate
thereof.
[0179] In another preferred embodiment of the compound according to
the invention of general Formula (I) is a compound wherein
R.sub.5 and R.sub.5' taken together with the connecting C-atom may
form a substituted or unsubstituted cycloalkyl or a substituted or
unsubstituted non-aromatic heterocyclyl; optionally in form of one
of the stereoisomers, preferably enantiomers or diastereomers, a
racemate or in form of a mixture of at least two of the
stereoisomers, preferably enantiomers and/or diastereomers, in any
mixing ratio, or a corresponding salt thereof, or a corresponding
solvate thereof.
[0180] In another preferred embodiment of the compound according to
the invention of general Formula (I) is a compound wherein
R.sub.5 and R.sub.5' taken together with the connecting C-atom may
form a substituted or unsubstituted cycloalkyl or a substituted or
unsubstituted heterocyclyl, while m is 1, X is a bond, n is 0 and
R.sub.2 is hydrogen, optionally in form of one of the
stereoisomers, preferably enantiomers or diastereomers, a racemate
or in form of a mixture of at least two of the stereoisomers,
preferably enantiomers and/or diastereomers, in any mixing ratio,
or a corresponding salt thereof, or a corresponding solvate
thereof.
[0181] In another preferred embodiment of the compound according to
the invention of general Formula (I) is a compound wherein
R.sub.5 and R.sub.5' taken together with the connecting C-atom may
form a substituted or unsubstituted cycloalkyl or a substituted or
unsubstituted non-aromatic heterocyclyl, while m is 1, X is a bond,
n is 0 and R.sub.2 is hydrogen, optionally in form of one of the
stereoisomers, preferably enantiomers or diastereomers, a racemate
or in form of a mixture of at least two of the stereoisomers,
preferably enantiomers and/or diastereomers, in any mixing ratio,
or a corresponding salt thereof, or a corresponding solvate
thereof.
[0182] In another preferred embodiment of the compound according to
the invention of general Formula (I) is a compound wherein
R.sub.6 and R.sub.6' are independently selected from hydrogen,
substituted or unsubstituted C.sub.1-6 alkyl, substituted or
unsubstituted C.sub.2-6 alkenyl, substituted or unsubstituted
C.sub.2-6 alkynyl, --CHOR.sub.10 and --C(O)OR.sub.10; optionally in
form of one of the stereoisomers, preferably enantiomers or
diastereomers, a racemate or in form of a mixture of at least two
of the stereoisomers, preferably enantiomers and/or diastereomers,
in any mixing ratio, or a corresponding salt thereof, or a
corresponding solvate thereof.
[0183] In another preferred embodiment of the compound according to
the invention of general Formula (I) is a compound wherein
R.sub.7 is selected from hydrogen, substituted or unsubstituted
C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl and
substituted or unsubstituted C.sub.2-6 alkynyl; optionally in form
of one of the stereoisomers, preferably enantiomers or
diastereomers, a racemate or in form of a mixture of at least two
of the stereoisomers, preferably enantiomers and/or diastereomers,
in any mixing ratio, or a corresponding salt thereof, or a
corresponding solvate thereof.
[0184] In another preferred embodiment of the compound according to
the invention of general Formula (I) is a compound wherein
R.sub.8 is selected from hydrogen, substituted or unsubstituted
C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl and
substituted or unsubstituted C.sub.2-6 alkynyl; optionally in form
of one of the stereoisomers, preferably enantiomers or
diastereomers, a racemate or in form of a mixture of at least two
of the stereoisomers, preferably enantiomers and/or diastereomers,
in any mixing ratio, or a corresponding salt thereof, or a
corresponding solvate thereof.
[0185] In another preferred embodiment of the compound according to
the invention of general Formula (I) is a compound wherein
R.sub.9 is selected from hydrogen, substituted or unsubstituted
C.sub.1-9 alkyl, substituted or unsubstituted C.sub.2-9 alkenyl and
substituted or unsubstituted C.sub.2-9 alkynyl; optionally in form
of one of the stereoisomers, preferably enantiomers or
diastereomers, a racemate or in form of a mixture of at least two
of the stereoisomers, preferably enantiomers and/or diastereomers,
in any mixing ratio, or a corresponding salt thereof, or a
corresponding solvate thereof.
[0186] In another preferred embodiment of the compound according to
the invention of general Formula (I) is a compound wherein
R.sub.10 is selected from hydrogen, substituted or unsubstituted
C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl and
substituted or unsubstituted C.sub.2-6 alkynyl; optionally in form
of one of the stereoisomers, preferably enantiomers or
diastereomers, a racemate or in form of a mixture of at least two
of the stereoisomers, preferably enantiomers and/or diastereomers,
in any mixing ratio, or a corresponding salt thereof, or a
corresponding solvate thereof.
[0187] In another preferred embodiment of the compound according to
the invention of general Formula (I) is a compound wherein
R.sub.11, R.sub.11' and R.sub.11'' are independently selected from
hydrogen, unsubstituted C.sub.1-6 alkyl, unsubstituted C.sub.2-6
alkenyl and unsubstituted C.sub.2-6 alkynyl; and wherein
R.sub.11''' is selected from hydrogen, unsubstituted C.sub.1-6
alkyl, unsubstituted C.sub.2-6 alkenyl, unsubstituted C.sub.2-6
alkynyl and -Boc; optionally in form of one of the stereoisomers,
preferably enantiomers or diastereomers, a racemate or in form of a
mixture of at least two of the stereoisomers, preferably
enantiomers and/or diastereomers, in any mixing ratio, or a
corresponding salt thereof, or a corresponding solvate thereof.
[0188] In another preferred embodiment of the compound according to
the invention of general Formula (I) is a compound wherein
R.sub.11, R.sub.11' and R.sub.11'' are independently selected from
hydrogen, unsubstituted C.sub.1-6 alkyl, unsubstituted C.sub.2-6
alkenyl and unsubstituted C.sub.2-6 alkynyl; optionally in form of
one of the stereoisomers, preferably enantiomers or diastereomers,
a racemate or in form of a mixture of at least two of the
stereoisomers, preferably enantiomers and/or diastereomers, in any
mixing ratio, or a corresponding salt thereof, or a corresponding
solvate thereof.
[0189] In another preferred embodiment of the compound according to
the invention of general Formula (I) is a compound wherein
R.sub.11''' is selected from hydrogen, unsubstituted C.sub.1-6
alkyl, unsubstituted C.sub.2-6 alkenyl, unsubstituted C.sub.2-6
alkynyl and -Boc; optionally in form of one of the stereoisomers,
preferably enantiomers or diastereomers, a racemate or in form of a
mixture of at least two of the stereoisomers, preferably
enantiomers and/or diastereomers, in any mixing ratio, or a
corresponding salt thereof, or a corresponding solvate thereof.
[0190] In another preferred embodiment of the compound according to
the invention of general Formula (I) is a compound wherein
R.sub.12, R.sub.12' and R.sub.12'' are independently selected from
hydrogen, unsubstituted C.sub.1-6 alkyl, unsubstituted C.sub.2-6
alkenyl and unsubstituted C.sub.2-6 alkynyl; and wherein
R.sub.12''' is selected from hydrogen, unsubstituted C.sub.1-6
alkyl, unsubstituted C.sub.2-6 alkenyl, unsubstituted C.sub.2-6
alkynyl and -Boc; optionally in form of one of the stereoisomers,
preferably enantiomers or diastereomers, a racemate or in form of a
mixture of at least two of the stereoisomers, preferably
enantiomers and/or diastereomers, in any mixing ratio, or a
corresponding salt thereof, or a corresponding solvate thereof.
[0191] In another preferred embodiment of the compound according to
the invention of general Formula (I) is a compound wherein
R.sub.12, R.sub.12' and R.sub.12'' are independently selected from
hydrogen, unsubstituted C.sub.1-6 alkyl, unsubstituted C.sub.2-6
alkenyl and unsubstituted C.sub.2-6 alkynyl; optionally in form of
one of the stereoisomers, preferably enantiomers or diastereomers,
a racemate or in form of a mixture of at least two of the
stereoisomers, preferably enantiomers and/or diastereomers, in any
mixing ratio, or a corresponding salt thereof, or a corresponding
solvate thereof.
[0192] In another preferred embodiment of the compound according to
the invention of general Formula (I) is a compound wherein
R.sub.12''' is selected from hydrogen, unsubstituted C.sub.1-6
alkyl, unsubstituted C.sub.2-6 alkenyl, unsubstituted C.sub.2-6
alkynyl and -Boc; optionally in form of one of the stereoisomers,
preferably enantiomers or diastereomers, a racemate or in form of a
mixture of at least two of the stereoisomers, preferably
enantiomers and/or diastereomers, in any mixing ratio, or a
corresponding salt thereof, or a corresponding solvate thereof.
[0193] In another preferred embodiment of the compound according to
the invention of general Formula (I) is a compound wherein
R.sub.13, are independently selected from hydrogen, unsubstituted
C.sub.1-6 alkyl, unsubstituted C.sub.2-6 alkenyl, and unsubstituted
C.sub.2-6 alkynyl; R.sub.13''' is selected from hydrogen,
unsubstituted C.sub.1-6 alkyl, unsubstituted C.sub.2-6 alkenyl,
unsubstituted C.sub.2-6 alkynyl and -Boc; optionally in form of one
of the stereoisomers, preferably enantiomers or diastereomers, a
racemate or in form of a mixture of at least two of the
stereoisomers, preferably enantiomers and/or diastereomers, in any
mixing ratio, or a corresponding salt thereof, or a corresponding
solvate thereof.
[0194] In another preferred embodiment of the compound according to
the invention of general Formula (I) is a compound wherein
R.sub.13, are independently selected from hydrogen, unsubstituted
C.sub.1-6 alkyl, unsubstituted C.sub.2-6 alkenyl, and unsubstituted
C.sub.2-6 alkynyl; optionally in form of one of the stereoisomers,
preferably enantiomers or diastereomers, a racemate or in form of a
mixture of at least two of the stereoisomers, preferably
enantiomers and/or diastereomers, in any mixing ratio, or a
corresponding salt thereof, or a corresponding solvate thereof.
[0195] In another preferred embodiment of the compound according to
the invention of general Formula (I) is a compound wherein
R.sub.13''' is selected from hydrogen, unsubstituted C.sub.1-6
alkyl, unsubstituted C.sub.2-6 alkenyl, unsubstituted C.sub.2-6
alkynyl and -Boc; optionally in form of one of the stereoisomers,
preferably enantiomers or diastereomers, a racemate or in form of a
mixture of at least two of the stereoisomers, preferably
enantiomers and/or diastereomers, in any mixing ratio, or a
corresponding salt thereof, or a corresponding solvate thereof.
[0196] In another preferred embodiment of the compound according to
the invention of general Formula (I) is a compound wherein
R.sub.14, R.sub.14' and R.sub.14'' are independently selected from
hydrogen, unsubstituted C.sub.1-6 alkyl, unsubstituted C.sub.2-6
alkenyl, unsubstituted C.sub.2-6 alkynyl, unsubstituted aryl,
unsubstituted cycloalkyl and unsubstituted heterocyclyl; and
wherein R.sub.14''' is selected from hydrogen, unsubstituted
C.sub.1-6 alkyl, unsubstituted C.sub.2-6 alkenyl, unsubstituted
C.sub.2-6 alkynyl and -Boc; optionally in form of one of the
stereoisomers, preferably enantiomers or diastereomers, a racemate
or in form of a mixture of at least two of the stereoisomers,
preferably enantiomers and/or diastereomers, in any mixing ratio,
or a corresponding salt thereof, or a corresponding solvate
thereof.
[0197] In another preferred embodiment of the compound according to
the invention of general Formula (I) is a compound wherein
R.sub.14, R.sub.14' and R.sub.14'' are independently selected from
hydrogen, unsubstituted C.sub.1-6 alkyl, unsubstituted C.sub.2-6
alkenyl, unsubstituted C.sub.2-6 alkynyl, unsubstituted aryl,
unsubstituted cycloalkyl and unsubstituted heterocycyl; optionally
in form of one of the stereoisomers, preferably enantiomers or
diastereomers, a racemate or in form of a mixture of at least two
of the stereoisomers, preferably enantiomers and/or diastereomers,
in any mixing ratio, or a corresponding salt thereof, or a
corresponding solvate thereof.
[0198] In another preferred embodiment of the compound according to
the invention of general Formula (I) is a compound wherein
R.sub.14''' is selected from hydrogen, unsubstituted C.sub.1-6
alkyl, unsubstituted C.sub.2-6 alkenyl, unsubstituted C.sub.2-6
alkynyl and -Boc; optionally in form of one of the stereoisomers,
preferably enantiomers or diastereomers, a racemate or in form of a
mixture of at least two of the stereoisomers, preferably
enantiomers and/or diastereomers, in any mixing ratio, or a
corresponding salt thereof, or a corresponding solvate thereof.
[0199] In another preferred embodiment of the compound according to
the invention of general Formula (I) is a compound wherein
R.sub.x is selected from halogen or substituted or unsubstituted
C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl
substituted or unsubstituted C.sub.2-6 alkynyl, and --OR.sub.7;
R.sub.x' is selected from hydrogen, halogen or substituted or
unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted
C.sub.2-6 alkenyl and substituted or unsubstituted C.sub.2-6
alkynyl; optionally in form of one of the stereoisomers, preferably
enantiomers or diastereomers, a racemate or in form of a mixture of
at least two of the stereoisomers, preferably enantiomers and/or
diastereomers, in any mixing ratio, or a corresponding salt
thereof, or a corresponding solvate thereof.
[0200] In another preferred embodiment of the compound according to
the invention of general Formula (I) is a compound wherein
R.sub.x is selected from halogen or substituted or unsubstituted
C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl
substituted or unsubstituted C.sub.2-6 alkynyl, and --OR.sub.7;
optionally in form of one of the stereoisomers, preferably
enantiomers or diastereomers, a racemate or in form of a mixture of
at least two of the stereoisomers, preferably enantiomers and/or
diastereomers, in any mixing ratio, or a corresponding salt
thereof, or a corresponding solvate thereof.
[0201] In another preferred embodiment of the compound according to
the invention of general Formula (I) is a compound wherein
R.sub.x' is selected from hydrogen, halogen or substituted or
unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted
C.sub.2-6 alkenyl and substituted or unsubstituted C.sub.2-6
alkynyl; optionally in form of one of the stereoisomers, preferably
enantiomers or diastereomers, a racemate or in form of a mixture of
at least two of the stereoisomers, preferably enantiomers and/or
diastereomers, in any mixing ratio, or a corresponding salt
thereof, or a corresponding solvate thereof.
[0202] In another preferred embodiment of the compound according to
the invention of general Formula (I), is a compound wherein
R.sub.1 is
##STR00034##
[0203] m is 1, 2, 3, 4 or 5; n is 0, 1, 2, 3, 4 or 5; p is 0 or 1;
q is 0, 1 or 2; r is 0, 1 or 2; X is a bond,
--C(R.sub.xR.sub.x')--, --C(O)--, --O--, --C(O)NR.sub.7--,
--NR.sub.7C(O)-- or --C(O)O--; R.sub.1' is selected from
substituted or unsubstituted C.sub.1-6 alkyl, substituted or
unsubstituted C.sub.2-6 alkenyl, substituted or unsubstituted
C.sub.2-6 alkynyl, substituted or unsubstituted cycloalkyl,
substituted or unsubstituted aryl and substituted or unsubstituted
heterocyclyl; wherein the C.sub.1-6 alkyl is preferably selected
from methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl and
2-methylpropyl; more preferably the C.sub.1-6 alkyl is methyl,
ethyl or isopropyl; and/or the C.sub.2-6-alkenyl is preferably
selected from ethylene, propylene, butylene, pentylene and
hexylene; and/or the C.sub.2-6-alkynyl is preferably selected from
ethyne, propyne, butyne, pentyne and hexyne; and/or the aryl is
selected from phenyl, naphtyl, or anthracene; preferably is napthyl
or phenyl; more preferably is phenyl; and/or the heterocyclyl is a
heterocyclic ring system of one or more saturated or unsaturated
rings of which at least one ring contains one or more heteroatoms
from the group consisting of nitrogen, oxygen and/or sulfur in the
ring; preferably is a heterocyclic ring system of one or two
saturated or unsaturated rings of which at least one ring contains
one or more heteroatoms from the group consisting of nitrogen,
oxygen and/or sulfur in the ring, more preferably is selected from
imidazole, oxadiazole, tetrazole, pyridine, pyrimidine, piperidine,
piperazine, benzofuran, benzimidazole, indazole, benzothiazole,
benzodiazole, thiazole, benzothiazole, tetrahydropyrane,
morpholine, indoline, furan, triazole, isoxazole, pyrazole,
thiophene, benzothiophene, pyrrole, pyrazine,
pyrrolo[2,3b]pyridine, quinoline, isoquinoline, phthalazine,
benzo-1,2,5-thiadiazole, indole, benzotriazole, benzoxazole
oxopyrrolidine, pyrimidine, benzodioxolane, benzodioxane, carbazole
and quinazoline; and/or the cycloalkyl is C.sub.3-8 cycloalkyl like
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or
cyclooctyl; preferably is C.sub.3-7 cycloalkyl like cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl; more
preferably from C.sub.3-6 cycloalkyl like cyclopropyl, cyclobutyl,
cyclopentyl or cyclohexyl; [0204] and/or R.sub.2 is selected from
hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted
or unsubstituted C.sub.2-6 alkenyl, substituted or unsubstituted
C.sub.2-6 alkynyl, substituted or unsubstituted cycloalkyl,
substituted or unsubstituted aryl and substituted or unsubstituted
heterocyclyl, wherein the C.sub.1-6 alkyl is preferably selected
from methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl and
2-methylpropyl; more preferably the C.sub.1-6 alkyl is isopropyl,
isobutyl, tert-butyl or 2.2-dimethylpropyl; and/or the
C.sub.2-6-alkenyl is preferably selected from ethylene, propylene,
butylene, pentylene and hexylene; and/or the C.sub.2-6-alkynyl is
preferably selected from ethyne, propyne, butyne, pentyne and
hexyne; and/or the aryl is selected from phenyl, naphtyl, or
anthracene; preferably is napthyl or phenyl; more preferably is
phenyl; and/or the heterocyclyl is a heterocyclic ring system of
one or more saturated or unsaturated rings of which at least one
ring contains one or more heteroatoms from the group consisting of
nitrogen, oxygen and/or sulfur in the ring; preferably is a
heterocyclic ring system of one or two saturated or unsaturated
rings of which at least one ring contains one or more heteroatoms
from the group consisting of nitrogen, oxygen and/or sulfur in the
ring, more preferably is selected from imidazole, oxadiazole,
tetrazole, pyridine, pyrimidine, piperidine, piperazine,
benzofuran, benzimidazole, indazole, benzothiazole, benzodiazole,
thiazole, benzothiazole, tetrahydropyrane, morpholine, indoline,
furan, triazole, isoxazole, pyrazole, thiophene, benzothiophene,
pyrrole, pyrazine, pyrrolo[2,3b]pyridine, quinoline, isoquinoline,
phthalazine, benzo-1,2,5-thiadiazole, indole, benzotriazole,
benzoxazole oxopyrrolidine, pyrimidine, benzodioxolane,
benzodioxane, carbazole and quinazoline; and/or the cycloalkyl is
C.sub.3-8 cycloalkyl like cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, cycloheptyl, or cyclooctyl; preferably is C.sub.3-7
cycloalkyl like cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
or cycloheptyl; more preferably from C.sub.3-6 cycloalkyl like
cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; [0205] and/or
R.sub.3 is selected from substituted or unsubstituted C.sub.1-6
alkyl, substituted or unsubstituted C.sub.2-6 alkenyl and
substituted or unsubstituted C.sub.2-6 alkynyl; [0206] wherein the
C.sub.1-6 alkyl is preferably selected from methyl, ethyl, propyl,
butyl, pentyl, hexyl, isopropyl and 2-methylpropyl; the C.sub.1-6
alkyl is preferably methyl; and/or the C.sub.2-6-alkenyl is
preferably selected from ethylene, propylene, butylene, pentylene
and hexylene; and/or the C.sub.2-6-alkynyl is preferably selected
from ethyne, propyne, butyne, pentyne and hexyne; and/or R.sub.3'
is selected from hydrogen, substituted or unsubstituted C.sub.1-6
alkyl, substituted or unsubstituted C.sub.2-6 alkenyl and
substituted or unsubstituted C.sub.2-6 alkynyl; [0207] wherein the
C.sub.1-6 alkyl is preferably selected from methyl, ethyl, propyl,
butyl, pentyl, hexyl, isopropyl and 2-methylpropyl; the C.sub.1-6
alkyl is preferably methyl; and/or the C.sub.2-6-alkenyl is
preferably selected from ethylene, propylene, butylene, pentylene
and hexylene; and/or the C.sub.2-6-alkynyl is preferably selected
from ethyne, propyne, butyne, pentyne and hexyne; and/or R.sub.3
and R.sub.3' form together with the carbon atom to which they are
attached a substituted or unsubstituted cycloalkyl; [0208] wherein
the cycloalkyl is C.sub.3-8 cycloalkyl like cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl;
preferably is C.sub.3-7 cycloalkyl like cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, or cycloheptyl; more preferably from
C.sub.3-6 cycloalkyl like cyclopropyl, cyclobutyl, cyclopentyl or
cyclohexyl; more preferably the cycloalkyl is cyclopropyl; and/or
R.sub.4 and R.sub.4' are independently selected from hydrogen,
substituted or unsubstituted C.sub.1-6 alkyl, substituted or
unsubstituted C.sub.2-6 alkenyl, substituted or unsubstituted
C.sub.2-6 alkynyl, --CHOR.sub.9 and --C(O)OR.sub.9; wherein the
C.sub.1-6 alkyl is preferably selected from methyl, ethyl, propyl,
butyl, pentyl, hexyl, isopropyl and 2-methylpropyl; and/or the
C.sub.2-6-alkenyl is preferably selected from ethylene, propylene,
butylene, pentylene and hexylene; and/or the C.sub.2-6-alkynyl is
preferably selected from ethyne, propyne, butyne, pentyne and
hexyne; and/or R.sub.5 and R.sub.5' are independently selected from
hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted
or unsubstituted C.sub.2-6 alkenyl, substituted or unsubstituted
C.sub.2-6 alkynyl, substituted or unsubstituted cycloalkyl,
substituted or unsubstituted aryl, substituted or unsubstituted
heterocyclyl, --CHOR.sub.8 and --C(O)OR.sub.8; alternatively
R.sub.5 and R.sub.5' taken together with the connecting C-atom may
form a substituted or unsubstituted cycloalkyl or a substituted or
unsubstituted heterocyclyl; wherein the C.sub.1-6 alkyl is
preferably selected from methyl, ethyl, propyl, butyl, pentyl,
hexyl, isopropyl and 2-methylpropyl; and/or the C.sub.2-6-alkenyl
is preferably selected from ethylene, propylene, butylene,
pentylene and hexylene; and/or the C.sub.2-6-alkynyl is preferably
selected from ethyne, propyne, butyne, pentyne and hexyne; and/or
the aryl is selected from phenyl, naphtyl, or anthracene;
preferably is napthyl or phenyl; and/or the heterocyclyl is a
heterocyclic ring system of one or more saturated or unsaturated
rings of which at least one ring contains one or more heteroatoms
from the group consisting of nitrogen, oxygen and/or sulfur in the
ring; preferably is a heterocyclic ring system of one or two
saturated or unsaturated rings of which at least one ring contains
one or more heteroatoms from the group consisting of nitrogen,
oxygen and/or sulfur in the ring, more preferably is selected from
imidazole, oxadiazole, tetrazole, pyridine, pyrimidine, piperidine,
piperazine, benzofuran, benzimidazole, indazole, benzothiazole,
benzodiazole, thiazole, benzothiazole, tetrahydropyrane,
morpholine, indoline, furan, triazole, isoxazole, pyrazole,
thiophene, benzothiophene, pyrrole, pyrazine,
pyrrolo[2,3b]pyridine, quinoline, isoquinoline, phthalazine,
benzo-1,2,5-thiadiazole, indole, benzotriazole, benzoxazole
oxopyrrolidine, pyrimidine, benzodioxolane, benzodioxane, carbazole
and quinazoline; preferably the heterocyclyl is a non-aromatic
heterocyclyl; and/or the cycloalkyl is C.sub.3-8 cycloalkyl like
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or
cyclooctyl; preferably is C.sub.3-7 cycloalkyl like cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl; more
preferably from C.sub.3-6 cycloalkyl like cyclopropyl, cyclobutyl,
cyclopentyl or cyclohexyl; and/or R.sub.6 and R.sub.6' are
independently selected from hydrogen, substituted or unsubstituted
C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl,
substituted or unsubstituted C.sub.2-6 alkynyl, --CHOR.sub.10 and
--C(O)OR.sub.10; wherein the C.sub.1-6 alkyl is preferably selected
from methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl and
2-methylpropyl; and/or the C.sub.2-6-alkenyl is preferably selected
from ethylene, propylene, butylene, pentylene and hexylene; and/or
the C.sub.2-6-alkynyl is preferably selected from ethyne, propyne,
butyne, pentyne and hexyne; and/or R.sub.7 is selected from
hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted
or unsubstituted C.sub.2-6 alkenyl and substituted or unsubstituted
C.sub.2-6 alkynyl; wherein the C.sub.1-6 alkyl is preferably
selected from methyl, ethyl, propyl, butyl, pentyl, hexyl,
isopropyl and 2-methylpropyl; and/or the C.sub.2-6-alkenyl is
preferably selected from ethylene, propylene, butylene, pentylene
and hexylene; and/or the C.sub.2-6--alkynyl is preferably selected
from ethyne, propyne, butyne, pentyne and hexyne; and/or R.sub.8 is
selected from hydrogen, substituted or unsubstituted C.sub.1-6
alkyl, substituted or unsubstituted C.sub.2-6 alkenyl and
substituted or unsubstituted C.sub.2 alkynyl; wherein the C.sub.1-6
alkyl is preferably selected from methyl, ethyl, propyl, butyl,
pentyl, hexyl, isopropyl and 2-methylpropyl; and/or the
C.sub.2-6-alkenyl is preferably selected from ethylene, propylene,
butylene, pentylene and hexylene; and/or the C.sub.2-6-alkynyl is
preferably selected from ethyne, propyne, butyne, pentyne and
hexyne; and/or R.sub.9 is selected from hydrogen, substituted or
unsubstituted C.sub.1-9 alkyl, substituted or unsubstituted
C.sub.2-9 alkenyl and substituted or unsubstituted C.sub.2-9
alkynyl; wherein the C.sub.1-6 alkyl is preferably selected from
methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl and
2-methylpropyl; and/or the C.sub.2-6-alkenyl is preferably selected
from ethylene, propylene, butylene, pentylene and hexylene; and/or
the C.sub.2-6-alkynyl is preferably selected from ethyne, propyne,
butyne, pentyne and hexyne; and/or R.sub.10 is selected from
hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted
or unsubstituted C.sub.2-6 alkenyl and substituted or unsubstituted
C.sub.2-6 alkynyl; wherein the C.sub.1-6 alkyl is preferably
selected from methyl, ethyl, propyl, butyl, pentyl, hexyl,
isopropyl and 2-methylpropyl; and/or the C.sub.2-6-alkenyl is
preferably selected from ethylene, propylene, butylene, pentylene
and hexylene; and/or the C.sub.2-6-alkynyl is preferably selected
from ethyne, propyne, butyne, pentyne and hexyne; and/or R.sub.11,
R.sub.11' and R.sub.11'' are independently selected from hydrogen,
unsubstituted C.sub.1-6 alkyl, unsubstituted C.sub.2-6 alkenyl and
unsubstituted C.sub.2-6 alkynyl; and wherein R.sub.11''' is
selected from hydrogen, unsubstituted C.sub.1-6 alkyl,
unsubstituted C.sub.2-6 alkenyl, unsubstituted C.sub.2-6 alkynyl
and -Boc; wherein the C.sub.1-6 alkyl is preferably selected from
methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl and
2-methylpropyl; and/or the C.sub.2-6-alkenyl is preferably selected
from ethylene, propylene, butylene, pentylene and hexylene; and/or
the C.sub.2-6-alkynyl is preferably selected from ethyne, propyne,
butyne, pentyne and hexyne; and/or R.sub.12, R.sub.12' and
R.sub.12'' are independently selected from hydrogen, unsubstituted
C.sub.1-6 alkyl, unsubstituted C.sub.2-6 alkenyl and unsubstituted
C.sub.2-6 alkynyl; and wherein R.sub.12''' is selected from
hydrogen, unsubstituted C.sub.1-6 alkyl, unsubstituted C.sub.2-6
alkenyl, unsubstituted C.sub.2-6 alkynyl and -Boc; wherein the
C.sub.1-6 alkyl is preferably selected from methyl, ethyl, propyl,
butyl, pentyl, hexyl, isopropyl and 2-methylpropyl; and/or the
C.sub.2-6-alkenyl is preferably selected from ethylene, propylene,
butylene, pentylene and hexylene; and/or the C.sub.2-6-alkynyl is
preferably selected from ethyne, propyne, butyne, pentyne and
hexyne; and/or R.sub.13, are independently selected from hydrogen,
unsubstituted C.sub.1-6 alkyl, unsubstituted C.sub.2-6 alkenyl, and
unsubstituted C.sub.2-6 alkynyl; R.sub.13''' is selected from
hydrogen, unsubstituted C.sub.1-6 alkyl, unsubstituted C.sub.2-6
alkenyl, unsubstituted C.sub.2-6 alkynyl and -Boc; wherein the
C.sub.1-6 alkyl is preferably selected from methyl, ethyl, propyl,
butyl, pentyl, hexyl, isopropyl and 2-methylpropyl; and/or the
C.sub.2-6-alkenyl is preferably selected from ethylene, propylene,
butylene, pentylene and hexylene; and/or the C.sub.2-6-alkynyl is
preferably selected from ethyne, propyne, butyne, pentyne and
hexyne; and/or R.sub.14, R.sub.14' and R.sub.14'' are independently
selected from hydrogen, unsubstituted C.sub.1-6 alkyl,
unsubstituted C.sub.2-6 alkenyl, unsubstituted C.sub.2-6 alkynyl,
unsubstituted aryl, unsubstituted cycloalkyl and unsubstituted
heterocyclyl; and wherein R.sub.14''' is selected from hydrogen,
unsubstituted C.sub.1-6 alkyl, unsubstituted C.sub.2-6 alkenyl,
unsubstituted C.sub.2-6 alkynyl and -Boc; wherein the C.sub.1-6
alkyl is preferably selected from methyl, ethyl, propyl, butyl,
pentyl, hexyl, isopropyl and 2-methylpropyl; and/or the
C.sub.2-6-alkenyl is preferably selected from ethylene, propylene,
butylene, pentylene and hexylene; and/or the C.sub.2-6-alkynyl is
preferably selected from ethyne, propyne, butyne, pentyne and
hexyne; and/or the aryl is selected from phenyl, naphtyl and
anthracene; preferably is napthyl or phenyl; and/or the
heterocyclyl is a heterocyclic ring system of one or more saturated
or unsaturated rings of which at least one ring contains one or
more heteroatoms from the group consisting of nitrogen, oxygen
and/or sulfur in the ring; preferably is a heterocyclic ring system
of one or two saturated or unsaturated rings of which at least one
ring contains one or more heteroatoms from the group consisting of
nitrogen, oxygen and/or sulfur in the ring, more preferably is
selected from imidazole, oxadiazole, tetrazole, pyridine,
pyrimidine, piperidine, piperazine, benzofuran, benzimidazole,
indazole, benzothiazole, benzodiazole, thiazole, benzothiazole,
tetrahydropyrane, morpholine, indoline, furan, triazole, isoxazole,
pyrazole, thiophene, benzothiophene, pyrrole, pyrazine,
pyrrolo[2,3b]pyridine, quinoline, isoquinoline, phthalazine,
benzo-1,2,5-thiadiazole, indole, benzotriazole, benzoxazole
oxopyrrolidine, pyrimidine, benzodioxolane, benzodioxane, carbazole
and quinazoline;
and/or the cycloalkyl is C.sub.3-8 cycloalkyl like cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl;
preferably is C.sub.3-7 cycloalkyl like cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, or cycloheptyl; more preferably from
C.sub.3-6 cycloalkyl like cyclopropyl, cyclobutyl, cyclopentyl or
cyclohexyl; and/or R.sub.x is selected from halogen or substituted
or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted
C.sub.2-6 alkenyl substituted or unsubstituted C.sub.2-6 alkynyl,
and --OR.sub.7; wherein the C.sub.1-6 alkyl is preferably selected
from methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl and
2-methylpropyl; and/or the C.sub.2-6-alkenyl is preferably selected
from ethylene, propylene, butylene, pentylene and hexylene; and/or
the C.sub.2-6-alkynyl is preferably selected from ethyne, propyne,
butyne, pentyne and hexyne; and/or R.sub.x' is selected from
hydrogen, halogen or substituted or unsubstituted C.sub.1-6 alkyl,
substituted or unsubstituted C.sub.2-6 alkenyl and substituted or
unsubstituted C.sub.2-6 alkynyl; wherein the C.sub.1-6 alkyl is
preferably selected from methyl, ethyl, propyl, butyl, pentyl,
hexyl, isopropyl and 2-methylpropyl; and/or the C.sub.2-6-alkenyl
is preferably selected from ethylene, propylene, butylene,
pentylene and hexylene; and/or the C.sub.2-6-alkynyl is preferably
selected from ethyne, propyne, butyne, pentyne and hexyne;
optionally in form of one of the stereoisomers, preferably
enantiomers or diastereomers, a racemate or in form of a mixture of
at least two of the stereoisomers, preferably enantiomers and/or
diastereomers, in any mixing ratio, or a corresponding salt
thereof, or a corresponding solvate thereof.
[0209] In another preferred embodiment of the invention according
to general Formula (I) the compound is a compound, wherein in
R.sub.1' as defined in any of the embodiments of the present
invention,
the C.sub.1-6 alkyl is preferably selected from methyl, ethyl,
propyl, butyl, pentyl, hexyl, isopropyl and 2-methylpropyl; more
preferably the C.sub.1-6 alkyl is methyl, ethyl or isopropyl;
and/or the C.sub.2-6-alkenyl is preferably selected from ethylene,
propylene, butylene, pentylene and hexylene; and/or the
C.sub.2-6-alkynyl is preferably selected from ethyne, propyne,
butyne, pentyne and hexyne; and/or the aryl is selected from
phenyl, naphtyl, or anthracene; preferably is napthyl or phenyl;
more preferably is phenyl; and/or the heterocyclyl is a
heterocyclic ring system of one or more saturated or unsaturated
rings of which at least one ring contains one or more heteroatoms
from the group consisting of nitrogen, oxygen and/or sulfur in the
ring; preferably is a heterocyclic ring system of one or two
saturated or unsaturated rings of which at least one ring contains
one or more heteroatoms from the group consisting of nitrogen,
oxygen and/or sulfur in the ring, more preferably is selected from
imidazole, oxadiazole, tetrazole, pyridine, pyrimidine, piperidine,
piperazine, benzofuran, benzimidazole, indazole, benzothiazole,
benzodiazole, thiazole, benzothiazole, tetrahydropyrane,
morpholine, indoline, furan, triazole, isoxazole, pyrazole,
thiophene, benzothiophene, pyrrole, pyrazine,
pyrrolo[2,3b]pyridine, quinoline, isoquinoline, phthalazine,
benzo-1,2,5-thiadiazole, indole, benzotriazole, benzoxazole
oxopyrrolidine, pyrimidine, benzodioxolane, benzodioxane, carbazole
and quinazoline; and/or the cycloalkyl is C.sub.3-8 cycloalkyl like
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or
cyclooctyl; preferably is C.sub.3-7 cycloalkyl like cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl; more
preferably from C.sub.3-6 cycloalkyl like cyclopropyl, cyclobutyl,
cyclopentyl or cyclohexyl; optionally in form of one of the
stereoisomers, preferably enantiomers or diastereomers, a racemate
or in form of a mixture of at least two of the stereoisomers,
preferably enantiomers and/or diastereomers, in any mixing ratio,
or a corresponding salt thereof, or a corresponding solvate
thereof.
[0210] In another preferred embodiment of the invention according
to general Formula (I) the compound is a compound, wherein in
R.sub.2 as defined in any of the embodiments of the present
invention,
the C.sub.1-6 alkyl is preferably selected from methyl, ethyl,
propyl, butyl, pentyl, hexyl, isopropyl and 2-methylpropyl; more
preferably the C.sub.1-6 alkyl is isopropyl, isobutyl, tert-butyl
or 2.2-dimethylpropyl; and/or the C.sub.2-6-alkenyl is preferably
selected from ethylene, propylene, butylene, pentylene and
hexytene; and/or the C.sub.2-6-alkynyl is preferably selected from
ethyne, propyne, butyne, pentyne and hexyne; and/or the aryl is
selected from phenyl, naphtyl, or anthracene; preferably is napthyl
or phenyl; more preferably is phenyl; and/or the heterocyclyl is a
heterocyclic ring system of one or more saturated or unsaturated
rings of which at least one ring contains one or more heteroatoms
from the group consisting of nitrogen, oxygen and/or sulfur in the
ring; preferably is a heterocyclic ring system of one or two
saturated or unsaturated rings of which at least one ring contains
one or more heteroatoms from the group consisting of nitrogen,
oxygen and/or sulfur in the ring, more preferably is selected from
imidazole, oxadiazole, tetrazole, pyridine, pyrimidine, piperidine,
piperazine, benzofuran, benzimidazole, indazole, benzothiazole,
benzodiazole, thiazole, benzothiazole, tetrahydropyrane,
morpholine, indoline, furan, triazole, isoxazole, pyrazole,
thiophene, benzothiophene, pyrrole, pyrazine,
pyrrolo[2,3b]pyridine, quinoline, isoquinoline, phthalazine,
benzo-1,2,5-thiadiazole, indole, benzotriazole, benzoxazole
oxopyrrolidine, pyrimidine, benzodioxolane, benzodioxane, carbazole
and quinazoline; and/or the cycloalkyl is C.sub.3-8 cycloalkyl like
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or
cyclooctyl; preferably is C.sub.3-7 cycloalkyl like cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl; more
preferably from C.sub.3-6 cycloalkyl like cyclopropyl, cyclobutyl,
cyclopentyl or cyclohexyl; optionally in form of one of the
stereoisomers, preferably enantiomers or diastereomers, a racemate
or in form of a mixture of at least two of the stereoisomers,
preferably enantiomers and/or diastereomers, in any mixing ratio,
or a corresponding salt thereof, or a corresponding solvate
thereof.
[0211] In another preferred embodiment of the invention according
to general Formula (I) the compound is a compound, wherein in
R.sub.3 as defined in any of the embodiments of the present
invention,
the C.sub.1-6 alkyl is preferably selected from methyl, ethyl,
propyl, butyl, pentyl, hexyl, isopropyl and 2-methylpropyl;
preferably the C.sub.1-6 alkyl is methyl; and/or the
C.sub.2-6-alkenyl is preferably selected from ethylene, propylene,
butylene, pentylene and hexylene; and/or the C.sub.2-6-alkynyl is
preferably selected from ethyne, propyne, butyne, pentyne and
hexyne; optionally in form of one of the stereoisomers, preferably
enantiomers or diastereomers, a racemate or in form of a mixture of
at least two of the stereoisomers, preferably enantiomers and/or
diastereomers, in any mixing ratio, or a corresponding salt
thereof, or a corresponding solvate thereof.
[0212] In another preferred embodiment of the invention according
to general Formula (I) the compound is a compound, wherein in
R.sub.3' as defined in any of the embodiments of the present
invention,
the C.sub.1-6 alkyl is preferably selected from methyl, ethyl,
propyl, butyl, pentyl, hexyl, isopropyl and 2-methylpropyl;
preferably the C.sub.1-6 alkyl is methyl; and/or the
C.sub.2-6-alkenyl is preferably selected from ethylene, propylene,
butylene, pentylene and hexylene; and/or the C.sub.2-6-alkynyl is
preferably selected from ethyne, propyne, butyne, pentyne and
hexyne; optionally in form of one of the stereoisomers, preferably
enantiomers or diastereomers, a racemate or in form of a mixture of
at least two of the stereoisomers, preferably enantiomers and/or
diastereomers, in any mixing ratio, or a corresponding salt
thereof, or a corresponding solvate thereof.
[0213] In another preferred embodiment of the invention according
to general Formula (I) the compound is a compound, wherein in
R.sub.3 and R.sub.3' as defined in any of the embodiments of the
present invention,
the cycloalkyl is C.sub.3-8 cycloalkyl like cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl;
preferably is C.sub.3-7 cycloalkyl like cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, or cycloheptyl; more preferably from
C.sub.3-6 cycloalkyl like cyclopropyl, cyclobutyl, cyclopentyl or
cyclohexyl; more preferably the cycloalkyl is cyclopropyl;
optionally in form of one of the stereoisomers, preferably
enantiomers or diastereomers, a racemate or in form of a mixture of
at least two of the stereoisomers, preferably enantiomers and/or
diastereomers, in any mixing ratio, or a corresponding salt
thereof, or a corresponding solvate thereof.
[0214] In another preferred embodiment of the invention according
to general Formula (I) the compound is a compound, wherein in
R.sub.4 and R.sub.4' as defined in any of the embodiments of the
present invention,
the C.sub.1-6 alkyl is preferably selected from methyl, ethyl,
propyl, butyl, pentyl, hexyl, isopropyl and 2-methylpropyl; and/or
the C.sub.2-6-alkenyl is preferably selected from ethylene,
propylene, butylene, pentylene and hexylene; and/or the
C.sub.2-6-alkynyl is preferably selected from ethyne, propyne,
butyne, pentyne and hexyne; optionally in form of one of the
stereoisomers, preferably enantiomers or diastereomers, a racemate
or in form of a mixture of at least two of the stereoisomers,
preferably enantiomers and/or diastereomers, in any mixing ratio,
or a corresponding salt thereof, or a corresponding solvate
thereof.
[0215] In another preferred embodiment of the invention according
to general Formula (I) the compound is a compound, wherein in
R.sub.5 and R.sub.5' as defined in any of the embodiments of the
present invention,
the C.sub.1-6 alkyl is preferably selected from methyl, ethyl,
propyl, butyl, pentyl, hexyl, isopropyl and 2-methylpropyl; and/or
the C.sub.2-6-alkenyl is preferably selected from ethylene,
propylene, butylene, pentylene and hexylene; and/or the
C.sub.2-6-alkynyl is preferably selected from ethyne, propyne,
butyne, pentyne and hexyne; and/or the aryl is selected from
phenyl, naphtyl, or anthracene; preferably is napthyl or phenyl;
and/or the heterocyclyl is a heterocyclic ring system of one or
more saturated or unsaturated rings of which at least one ring
contains one or more heteroatoms from the group consisting of
nitrogen, oxygen and/or sulfur in the ring; preferably is a
heterocyclic ring system of one or two saturated or unsaturated
rings of which at least one ring contains one or more heteroatoms
from the group consisting of nitrogen, oxygen and/or sulfur in the
ring, more preferably is selected from imidazole, oxadiazole,
tetrazole, pyridine, pyrimidine, piperidine, piperazine,
benzofuran, benzimidazole, indazole, benzothiazole, benzodiazole,
thiazole, benzothiazole, tetrahydropyrane, morpholine, indoline,
furan, triazole, isoxazole, pyrazole, thiophene, benzothiophene,
pyrrole, pyrazine, pyrrolo[2.3b]pyridine, quinoline, isoquinoline,
phthalazine, benzo-1,2,5-thiadiazole, indole, benzotriazole,
benzoxazole oxopyrrolidine, pyrimidine, benzodioxolane,
benzodioxane, carbazole and quinazoline; and/or the cycloalkyl is
C.sub.3-8 cycloalkyl like cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, cycloheptyl, or cyclooctyl; preferably is C.sub.3-7
cycloalkyl like cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
or cycloheptyl; more preferably from C.sub.3-6 cycloalkyl like
cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; optionally in
form of one of the stereoisomers, preferably enantiomers or
diastereomers, a racemate or in form of a mixture of at least two
of the stereoisomers, preferably enantiomers and/or diastereomers,
in any mixing ratio, or a corresponding salt thereof, or a
corresponding solvate thereof.
[0216] In another preferred embodiment of the invention according
to general Formula (I) the compound is a compound, wherein in
R.sub.5 and R.sub.5' forming with the connecting C-atom a
substituted or unsubstituted cycloalkyl or a substituted or
unsubstituted heterocyclyl, as defined in any of the embodiments of
the present invention,
the heterocyclyl is a heterocyclic ring system of one or more
saturated or unsaturated rings of which at least one ring contains
one or more heteroatoms from the group consisting of nitrogen,
oxygen and/or sulfur in the ring; preferably is a heterocyclic ring
system of one or two saturated or unsaturated rings of which at
least one ring contains one or more heteroatoms from the group
consisting of nitrogen, oxygen and/or sulfur in the ring, more
preferably is selected from imidazole, oxadiazole, tetrazole,
pyridine, pyrimidine, piperidine, piperazine, benzofuran,
benzimidazole, indazole, benzothiazole, benzodiazole, thiazole,
benzothiazole, tetrahydropyrane, morpholine, indoline, furan,
triazole, isoxazole, pyrazole, thiophene, benzothiophene, pyrrole,
pyrazine, pyrrolo[2,3b]pyridine, quinoline, isoquinoline,
phthalazine, benzo-1,2,5-thiadiazole, indole, benzotriazole,
benzoxazole oxopyrrolidine, pyrimidine, benzodioxolane,
benzodioxane, carbazole and quinazoline; the heterocyclyl is
preferably a non-aromatic heterocyclyl, and/or the cycloalkyl is
C.sub.3-8 cycloalkyl like cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, cycloheptyl, or cyclooctyl; preferably is C.sub.3-7
cycloalkyl like cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
or cycloheptyl; more preferably from C.sub.3-6 cycloalkyl like
cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; optionally in
form of one of the stereoisomers, preferably enantiomers or
diastereomers, a racemate or in form of a mixture of at least two
of the stereoisomers, preferably enantiomers and/or diastereomers,
in any mixing ratio, or a corresponding salt thereof, or a
corresponding solvate thereof.
[0217] In another preferred embodiment of the invention according
to general Formula (I) the compound is a compound, wherein in
R.sub.6 and R.sub.6' as defined in any of the embodiments of the
present invention,
the C.sub.1-6 alkyl is preferably selected from methyl, ethyl,
propyl, butyl, pentyl, hexyl, isopropyl and 2-methylpropyl; and/or
the C.sub.2-6-alkenyl is preferably selected from ethylene,
propylene, butylene, pentylene and hexylene; and/or the
C.sub.2-6-alkynyl is preferably selected from ethyne, propyne,
butyne, pentyne and hexyne; optionally in form of one of the
stereoisomers, preferably enantiomers or diastereomers, a racemate
or in form of a mixture of at least two of the stereoisomers,
preferably enantiomers and/or diastereomers, in any mixing ratio,
or a corresponding salt thereof, or a corresponding solvate
thereof.
[0218] In another preferred embodiment of the invention according
to general Formula (I) the compound is a compound, wherein in
R.sub.7 as defined in any of the embodiments of the present
invention,
the C.sub.1-6 alkyl is preferably selected from methyl, ethyl,
propyl, butyl, pentyl, hexyl, isopropyl and 2-methylpropyl; and/or
the C.sub.2-6-alkenyl is preferably selected from ethylene,
propylene, butylene, pentylene and hexylene; and/or the
C.sub.2-6-alkynyl is preferably selected from ethyne, propyne,
butyne, pentyne and hexyne; optionally in form of one of the
stereoisomers, preferably enantiomers or diastereomers, a racemate
or in form of a mixture of at least two of the stereoisomers,
preferably enantiomers and/or diastereomers, in any mixing ratio,
or a corresponding salt thereof, or a corresponding solvate
thereof.
[0219] In another preferred embodiment of the invention according
to general Formula (I) the compound is a compound, wherein in
R.sub.8 as defined in any of the embodiments of the present
invention,
the C.sub.1-6 alkyl is preferably selected from methyl, ethyl,
propyl, butyl, pentyl, hexyl, isopropyl and 2-methylpropyl; and/or
the C.sub.2-6-alkenyl is preferably selected from ethylene,
propylene, butylene, pentylene and hexylene; and/or the
C.sub.2-6-alkynyl is preferably selected from ethyne, propyne,
butyne, pentyne and hexyne; optionally in form of one of the
stereoisomers, preferably enantiomers or diastereomers, a racemate
or in form of a mixture of at least two of the stereoisomers,
preferably enantiomers and/or diastereomers, in any mixing ratio,
or a corresponding salt thereof, or a corresponding solvate
thereof.
[0220] In another preferred embodiment of the invention according
to general Formula (I) the compound is a compound, wherein in
R.sub.9 as defined in any of the embodiments of the present
invention,
the C.sub.1-6 alkyl is preferably selected from methyl, ethyl,
propyl, butyl, pentyl, hexyl, isopropyl and 2-methylpropyl; and/or
the C.sub.2-6-alkenyl is preferably selected from ethylene,
propylene, butylene, pentylene and hexylene; and/or the
C.sub.2-6-alkynyl is preferably selected from ethyne, propyne,
butyne, pentyne and hexyne; optionally in form of one of the
stereoisomers, preferably enantiomers or diastereomers, a racemate
or in form of a mixture of at least two of the stereoisomers,
preferably enantiomers and/or diastereomers, in any mixing ratio,
or a corresponding salt thereof, or a corresponding solvate
thereof.
[0221] In another preferred embodiment of the invention according
to general Formula (I) the compound is a compound, wherein in
R.sub.10 as defined in any of the embodiments of the present
invention,
the C.sub.1-6 alkyl is preferably selected from methyl, ethyl,
propyl, butyl, pentyl, hexyl, isopropyl and 2-methylpropyl; and/or
the C.sub.2-6-alkenyl is preferably selected from ethylene,
propylene, butylene, pentylene and hexylene; and/or the
C.sub.2-6-alkynyl is preferably selected from ethyne, propyne,
butyne, pentyne and hexyne; optionally in form of one of the
stereoisomers, preferably enantiomers or diastereomers, a racemate
or in form of a mixture of at least two of the stereoisomers,
preferably enantiomers and/or diastereomers, in any mixing ratio,
or a corresponding salt thereof, or a corresponding solvate
thereof.
[0222] In another preferred embodiment of the invention according
to general Formula (I) the compound is a compound, wherein in
R.sub.11, R.sub.11' and R.sub.11'' as defined in any of the
embodiments of the present invention,
the C.sub.1-6 alkyl is preferably selected from methyl, ethyl,
propyl, butyl, pentyl, hexyl, isopropyl and 2-methylpropyl; and/or
the C.sub.2-6-alkenyl is preferably selected from ethylene,
propylene, butylene, pentylene and hexylene; and/or the
C.sub.2-6-alkynyl is preferably selected from ethyne, propyne,
butyne, pentyne and hexyne; optionally in form of one of the
stereoisomers, preferably enantiomers or diastereomers, a racemate
or in form of a mixture of at least two of the stereoisomers,
preferably enantiomers and/or diastereomers, in any mixing ratio,
or a corresponding salt thereof, or a corresponding solvate
thereof.
[0223] In another preferred embodiment of the invention according
to general Formula (I) the compound is a compound, wherein in
R.sub.11''' as defined in any of the embodiments of the present
invention,
the C.sub.1-6 alkyl is preferably selected from methyl, ethyl,
propyl, butyl, pentyl, hexyl, isopropyl and 2-methylpropyl; and/or
the C.sub.2-6-alkenyl is preferably selected from ethylene,
propylene, butylene, pentylene and hexylene; and/or the
C.sub.2-6-alkynyl is preferably selected from ethyne, propyne,
butyne, pentyne and hexyne; optionally in form of one of the
stereoisomers, preferably enantiomers or diastereomers, a racemate
or in form of a mixture of at least two of the stereoisomers,
preferably enantiomers and/or diastereomers, in any mixing ratio,
or a corresponding salt thereof, or a corresponding solvate
thereof.
[0224] In another preferred embodiment of the invention according
to general Formula (I) the compound is a compound, wherein in
R.sub.12, R.sub.12' and R.sub.12'' as defined in any of the
embodiments of the present invention,
the C.sub.1-6 alkyl is preferably selected from methyl, ethyl,
propyl, butyl, pentyl, hexyl, isopropyl and 2-methylpropyl; and/or
the C.sub.2-6-alkenyl is preferably selected from ethylene,
propylene, butylene, pentylene and hexylene; and/or the
C.sub.2-6-alkynyl is preferably selected from ethyne, propyne,
butyne, pentyne and hexyne; optionally in form of one of the
stereoisomers, preferably enantiomers or diastereomers, a racemate
or in form of a mixture of at least two of the stereoisomers,
preferably enantiomers and/or diastereomers, in any mixing ratio,
or a corresponding salt thereof, or a corresponding solvate
thereof.
[0225] In another preferred embodiment of the invention according
to general Formula (I) the compound is a compound, wherein in
R.sub.12''' as defined in any of the embodiments of the present
invention,
the C.sub.1-6 alkyl is preferably selected from methyl, ethyl,
propyl, butyl, pentyl, hexyl, isopropyl and 2-methylpropyl; and/or
the C.sub.2-6-alkenyl is preferably selected from ethylene,
propylene, butylene, pentylene and hexylene; and/or the
C.sub.2-6-alkynyl is preferably selected from ethyne, propyne,
butyne, pentyne and hexyne; optionally in form of one of the
stereoisomers, preferably enantiomers or diastereomers, a racemate
or in form of a mixture of at least two of the stereoisomers,
preferably enantiomers and/or diastereomers, in any mixing ratio,
or a corresponding salt thereof, or a corresponding solvate
thereof.
[0226] In another preferred embodiment of the invention according
to general Formula (I) the compound is a compound, wherein in
R.sub.13 and R.sub.13''' as defined in any of the embodiments of
the present invention,
the C.sub.1-6 alkyl is preferably selected from methyl, ethyl,
propyl, butyl, pentyl, hexyl, isopropyl and 2-methylpropyl; and/or
the C.sub.2-6-alkenyl is preferably selected from ethylene,
propylene, butylene, pentylene and hexylene; and/or the
C.sub.2-6-alkynyl is preferably selected from ethyne, propyne,
butyne, pentyne and hexyne; optionally in form of one of the
stereoisomers, preferably enantiomers or diastereomers, a racemate
or in form of a mixture of at least two of the stereoisomers,
preferably enantiomers and/or diastereomers, in any mixing ratio,
or a corresponding salt thereof, or a corresponding solvate
thereof.
[0227] In another preferred embodiment of the invention according
to general Formula (I) the compound is a compound, wherein in
R.sub.14, R.sub.14' and R.sub.14'' as defined in any of the
embodiments of the present invention,
the C.sub.1-6 alkyl is preferably selected from methyl, ethyl,
propyl, butyl, pentyl, hexyl, isopropyl and 2-methylpropyl; and/or
the C.sub.2-6-alkenyl is preferably selected from ethylene,
propylene, butylene, pentylene and hexylene; and/or the
C.sub.2-6-alkynyl is preferably selected from ethyne, propyne,
butyne, pentyne and hexyne; and/or the aryl is selected from
phenyl, naphtyl and anthracene; preferably is napthyl or phenyl;
and/or the heterocyclyl is a heterocyclic ring system of one or
more saturated or unsaturated rings of which at least one ring
contains one or more heteroatoms from the group consisting of
nitrogen, oxygen and/or sulfur in the ring; preferably is a
heterocyclic ring system of one or two saturated or unsaturated
rings of which at least one ring contains one or more heteroatoms
from the group consisting of nitrogen, oxygen and/or sulfur in the
ring, more preferably is selected from imidazole, oxadiazole,
tetrazole, pyridine, pyrimidine, piperidine, piperazine,
benzofuran, benzimidazole, indazole, benzothiazole, benzodiazole,
thiazole, benzothiazole, tetrahydropyrane, morpholine, indoline,
furan, triazole, isoxazole, pyrazole, thiophene, benzothiophene,
pyrrole, pyrazine, pyrrolo[2,3b]pyridine, quinoline, isoquinoline,
phthalazine, benzo-1,2,5-thiadiazole, indole, benzotriazole,
benzoxazole oxopyrrolidine, pyrimidine, benzodioxolane,
benzodioxane, carbazole and quinazoline; and/or the cycloalkyl is
C.sub.3-8 cycloalkyl like cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, cycloheptyl, or cyclooctyl; preferably is C.sub.3-7
cycloalkyl like cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
or cycloheptyl; more preferably from C.sub.3-6 cycloalkyl like
cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; optionally in
form of one of the stereoisomers, preferably enantiomers or
diastereomers, a racemate or in form of a mixture of at least two
of the stereoisomers, preferably enantiomers and/or diastereomers,
in any mixing ratio, or a corresponding salt thereof, or a
corresponding solvate thereof.
[0228] In another preferred embodiment of the invention according
to general Formula (I) the compound is a compound, wherein in
R.sub.14''' as defined in any of the embodiments of the present
invention,
the C.sub.1-6 alkyl is preferably selected from methyl, ethyl,
propyl, butyl, pentyl, hexyl, isopropyl and 2-methylpropyl; and/or
the C.sub.2-6-alkenyl is preferably selected from ethylene,
propylene, butylene, pentylene and hexylene; and/or the
C.sub.2-6-alkynyl is preferably selected from ethyne, propyne,
butyne, pentyne and hexyne; optionally in form of one of the
stereoisomers, preferably enantiomers or diastereomers, a racemate
or in form of a mixture of at least two of the stereoisomers,
preferably enantiomers and/or diastereomers, in any mixing ratio,
or a corresponding salt thereof, or a corresponding solvate
thereof.
[0229] In another preferred embodiment of the invention according
to general Formula (I) the compound is a compound, wherein in
R.sub.x as defined in any of the embodiments of the present
invention,
the C.sub.1-6 alkyl is preferably selected from methyl, ethyl,
propyl, butyl, pentyl, hexyl, isopropyl and 2-methylpropyl; and/or
the C.sub.2-6-alkenyl is preferably selected from ethylene,
propylene, butylene, pentylene and hexylene; and/or the
C.sub.2-6-alkynyl is preferably selected from ethyne, propyne,
butyne, pentyne and hexyne; optionally in form of one of the
stereoisomers, preferably enantiomers or diastereomers, a racemate
or in form of a mixture of at least two of the stereoisomers,
preferably enantiomers and/or diastereomers, in any mixing ratio,
or a corresponding salt thereof, or a corresponding solvate
thereof.
[0230] In another preferred embodiment of the invention according
to general Formula (I) the compound is a compound, wherein in
R.sub.x, as defined in any of the embodiments of the present
invention,
the C.sub.1-6 alkyl is preferably selected from methyl, ethyl,
propyl, butyl, pentyl, hexyl, isopropyl and 2-methylpropyl; and/or
the C.sub.2-6-alkenyl is preferably selected from ethylene,
propylene, butylene, pentylene and hexylene; and/or the
C.sub.2-6-alkynyl is preferably selected from ethyne, propyne,
butyne, pentyne and hexyne; optionally in form of one of the
stereoisomers, preferably enantiomers or diastereomers, a racemate
or in form of a mixture of at least two of the stereoisomers,
preferably enantiomers and/or diastereomers, in any mixing ratio,
or a corresponding salt thereof, or a corresponding solvate
thereof.
[0231] In another preferred embodiment of the invention according
to general Formula (I) the compound is a compound, wherein
n is 0, 1, 2, 3, 4 or 5; preferably n is 0 or 1; optionally in form
of one of the stereoisomers, preferably enantiomers or
diastereomers, a racemate or in form of a mixture of at least two
of the stereoisomers, preferably enantiomers and/or diastereomers,
in any mixing ratio, or a corresponding salt thereof, or a
corresponding solvate thereof.
[0232] In another preferred embodiment of the invention according
to general Formula (I) the compound is a compound, wherein
m is 1, 2, 3, 4 or 5; preferably m is 1 or 2; optionally in form of
one of the stereoisomers, preferably enantiomers or diastereomers,
a racemate or in form of a mixture of at least two of the
stereoisomers, preferably enantiomers and/or diastereomers, in any
mixing ratio, or a corresponding salt thereof, or a corresponding
solvate thereof.
[0233] In another preferred embodiment of the invention according
to general Formula (I) the compound is a compound, wherein
p is 0 or 1; preferably p is 0; optionally in form of one of the
stereoisomers, preferably enantiomers or diastereomers, a racemate
or in form of a mixture of at least two of the stereoisomers,
preferably enantiomers and/or diastereomers, in any mixing ratio,
or a corresponding salt thereof, or a corresponding solvate
thereof.
[0234] In another preferred embodiment of the invention according
to general Formula (I) the compound is a compound, wherein
q is 0, 1 or 2; preferably q is 0 or 1; optionally in form of one
of the stereoisomers, preferably enantiomers or diastereomers, a
racemate or in form of a mixture of at least two of the
stereoisomers, preferably enantiomers and/or diastereomers, in any
mixing ratio, or a corresponding salt thereof, or a corresponding
solvate thereof.
[0235] In another preferred embodiment of the invention according
to general Formula (I) the compound is a compound, wherein
r is 0, 1 or 2; preferably r is 0 or 2; optionally in form of one
of the stereoisomers, preferably enantiomers or diastereomers, a
racemate or in form of a mixture of at least two of the
stereoisomers, preferably enantiomers and/or diastereomers, in any
mixing ratio, or a corresponding salt thereof, or a corresponding
solvate thereof.
[0236] In another preferred embodiment of the invention according
to general Formula (I) the compound is a compound, wherein
X is a bond, --C(R.sub.xR.sub.x)--, --C(O)--, --O--,
--C(O)NR.sub.7--, --NR.sub.7C(O)-- or --C(O)O--; preferably, X is a
bond or --O--; optionally in form of one of the stereoisomers,
preferably enantiomers or diastereomers, a racemate or in form of a
mixture of at least two of the stereoisomers, preferably
enantiomers and/or diastereomers, in any mixing ratio, or a
corresponding salt thereof, or a corresponding solvate thereof.
[0237] In another preferred embodiment of the invention according
to general Formula (I) the compound is a compound, wherein
Y is --CH.sub.2-- or --C(O)--;
[0238] optionally in form of one of the stereoisomers, preferably
enantiomers or diastereomers, a racemate or in form of a mixture of
at least two of the stereoisomers, preferably enantiomers and/or
diastereomers, in any mixing ratio, or a corresponding salt
thereof, or a corresponding solvate thereof.
[0239] In a further preferred embodiment of the invention according
to general Formula (I) the compound is a compound, wherein
X is a bond, --C(R.sub.xR.sub.x')--, --O--, --C(O)--,
--C(O)NR.sub.7--, --NR.sub.7C(O)-- or --C(O)O--; preferably X is a
bond and/or m is 1, 2, 3, 4 or 5; preferably m is 1 or 2; and/or n
is 0, 1, 2, 3, 4 or 5; preferably n is 0 or 1; and/or p is 0 or 1;
preferably p is 0; and/or q is 0, 1 or 2; preferably q is 0 or 1;
and/or r is 0, 1 or 2; preferably r is 0 or 2; optionally in form
of one of the stereoisomers, preferably enantiomers or
diastereomers, a racemate or in form of a mixture of at least two
of the stereoisomers, preferably enantiomers and/or diastereomers,
in any mixing ratio, or a corresponding salt thereof, or a
corresponding solvate thereof.
[0240] In a further preferred embodiment of the invention according
to general Formula (I) the compound is a compound, wherein
X is a bond, --C(R.sub.xR.sub.x')--, --O--, --C(O)--,
--C(O)NR.sub.7--, --NR.sub.7C(O)-- or --C(O)O--; preferably X is
--O-- and/or m is 1, 2, 3, 4 or 5; preferably m is 1 or 2; and/or n
is 0, 1, 2, 3, 4 or 5; preferably n is 0; and/or p is 0 or 1;
preferably p is 0; and/or q is 0, 1 or 2; preferably q is 0 or 1;
and/or r is 0, 1 or 2; preferably r is 0 or 2; optionally in form
of one of the stereoisomers, preferably enantiomers or
diastereomers, a racemate or in form of a mixture of at least two
of the stereoisomers, preferably enantiomers and/or diastereomers,
in any mixing ratio, or a corresponding salt thereof, or a
corresponding solvate thereof.
[0241] In another preferred embodiment of the invention according
to general Formula (I), the compound is a compound of Formula
(I')
##STR00035##
wherein R.sub.1 is
##STR00036##
m is 1, 2, 3, 4 or 5; p is 0 or 1; q is 0, 1 or 2; r is 0, 1 or 2;
X is a bond, --C(R.sub.xR.sub.x')--, --C(O)--, --O--,
--C(O)NR.sub.7--, --NR.sub.7C(O)-- or --C(O)O--; [0242] wherein
R.sub.x is selected from halogen or substituted or unsubstituted
C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl
substituted or unsubstituted C.sub.2-6 alkynyl, and --OR.sub.7;
[0243] R.sub.x' is selected from hydrogen, halogen or substituted
or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted
C.sub.2-6 alkenyl and substituted or unsubstituted C.sub.2-6
alkynyl; [0244] R.sub.7 is selected from hydrogen, substituted or
unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted
C.sub.2-6 alkenyl and substituted or unsubstituted C.sub.2-6
alkynyl;
Y is --CH.sub.2-- or --C(O)--;
[0245] R.sub.1' is selected from substituted or unsubstituted
C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl,
substituted or unsubstituted C.sub.2-6 alkynyl, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted aryl and
substituted or unsubstituted heterocyclyl; R.sub.2 is selected from
hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted
or unsubstituted C.sub.2-6 alkenyl, substituted or unsubstituted
C.sub.2-6 alkynyl, substituted or unsubstituted cycloalkyl,
substituted or unsubstituted aryl and substituted or unsubstituted
heterocyclyl; R.sub.3 is selected from substituted or unsubstituted
C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl and
substituted or unsubstituted C.sub.2-6 alkynyl; R.sub.3' is
selected from hydrogen, substituted or unsubstituted C.sub.1-6
alkyl, substituted or unsubstituted C.sub.2-6 alkenyl and
substituted or unsubstituted C.sub.2-6 alkynyl; alternatively,
R.sub.3 and R.sub.3' may form together with the carbon atom to
which they are attached a substituted or unsubstituted cycloalkyl;
R.sub.4 and R.sub.4' are independently selected from hydrogen,
substituted or unsubstituted C.sub.1-6 alkyl, substituted or
unsubstituted C.sub.2-6 alkenyl, substituted or unsubstituted
C.sub.2-6 alkynyl, --CHOR.sub.9 and --C(O)OR.sub.9; [0246] wherein
R.sub.9 is selected from hydrogen, substituted or unsubstituted
C.sub.1-9 alkyl, substituted or unsubstituted C.sub.2-9 alkenyl and
substituted or unsubstituted C.sub.2-9 alkynyl; R.sub.5 and
R.sub.5' are independently selected from hydrogen, substituted or
unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted
C.sub.2-6 alkenyl, substituted or unsubstituted C.sub.2-6 alkynyl,
substituted or unsubstituted cycloalkyl, substituted or
unsubstituted aryl, substituted or unsubstituted heterocyclyl,
--CHOR.sub.8 and --C(O)OR.sub.8; [0247] wherein R.sub.8 is selected
from hydrogen, substituted or unsubstituted C.sub.1-6 alkyl,
substituted or unsubstituted C.sub.2-6 alkenyl and substituted or
unsubstituted C.sub.2-6 alkynyl; alternatively R.sub.5 and R.sub.5'
taken together with the connecting C-atom may form a substituted or
unsubstituted cycloalkyl or a substituted or unsubstituted
heterocyclyl; optionally in form of one of the stereoisomers,
preferably enantiomers or diastereomers, a racemate or in form of a
mixture of at least two of the stereoisomers, preferably
enantiomers and/or diastereomers, in any mixing ratio, or a
corresponding salt thereof, or a corresponding solvate thereof.
[0248] In a further preferred embodiment of the invention according
to general Formula (I) the compound is a compound of Formula
(I.sup.2'),
##STR00037##
wherein
R.sub.1 is
##STR00038##
[0249] m is 1, 2, 3, 4 or 5; p is or 1; q is 0, 1 or 2; r is 0, 1
or 2; X is a bond, --C(R.sub.xR.sub.x')--, --C(O)--, --O--,
--C(O)NR.sub.7--, --NR.sub.7C(O)-- or --C(O)O--; [0250] wherein
R.sub.x is selected from halogen or substituted or unsubstituted
C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl
substituted or unsubstituted C.sub.2-6 alkynyl, and --OR.sub.7;
[0251] R.sub.x' is selected from hydrogen, halogen or substituted
or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted
C.sub.2-6 alkenyl and substituted or unsubstituted C.sub.2-6
alkynyl; [0252] R.sub.7 is selected from hydrogen, substituted or
unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted
C.sub.2-6 alkenyl and substituted or unsubstituted C.sub.2-6
alkynyl;
Y is --CH.sub.2-- or --C(O)--;
[0253] R.sub.1' is selected from substituted or unsubstituted
C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl,
substituted or unsubstituted C.sub.2-6 alkynyl, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted aryl and
substituted or unsubstituted heterocyclyl; R.sub.2 is selected from
hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted
or unsubstituted C.sub.2-6 alkenyl, substituted or unsubstituted
C.sub.2-6 alkynyl, substituted or unsubstituted cycloalkyl,
substituted or unsubstituted aryl and substituted or unsubstituted
heterocyclyl; R.sub.4 and R.sub.4' are independently selected from
hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted
or unsubstituted C.sub.2-6 alkenyl, substituted or unsubstituted
C.sub.2-6 alkynyl, --CHOR.sub.9 and --C(O)OR.sub.9; [0254] wherein
R.sub.9 is selected from hydrogen, substituted or unsubstituted
C.sub.1-9 alkyl, substituted or unsubstituted C.sub.2-9 alkenyl and
substituted or unsubstituted C.sub.2-9 alkynyl; R.sub.5 and
R.sub.5' are independently selected from hydrogen, substituted or
unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted
C.sub.2-6 alkenyl, substituted or unsubstituted C.sub.2-6 alkynyl,
substituted or unsubstituted cycloalkyl, substituted or
unsubstituted aryl, substituted or unsubstituted heterocydyl,
--CHOR.sub.8 and --C(O)OR.sub.8; [0255] wherein R.sub.8 is selected
from hydrogen, substituted or unsubstituted C.sub.1-6 alkyl,
substituted or unsubstituted C.sub.2-6 alkenyl and substituted or
unsubstituted C.sub.2-6 alkynyl; alternatively R.sub.5 and R.sub.5'
taken together with the connecting C-atom may form a substituted or
unsubstituted cycloalkyl or a substituted or unsubstituted
heterocyclyl; optionally in form of one of the stereoisomers,
preferably enantiomers or diastereomers, a racemate or in form of a
mixture of at least two of the stereoisomers, preferably
enantiomers and/or diastereomers, in any mixing ratio, or a
corresponding salt thereof, or a corresponding solvate thereof.
[0256] In a further preferred embodiment of the invention according
to general Formula (I) the compound is a compound of Formula
(I.sup.3'),
##STR00039##
wherein
R.sub.1 is
##STR00040##
[0257] m is 1, 2, 3, 4 or 5; p is 0 or 1; q is 0, 1 or 2; r is 0, 1
or 2; R.sub.1' is selected from substituted or unsubstituted
C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl,
substituted or unsubstituted C.sub.2-6 alkynyl, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted aryl and
substituted or unsubstituted heterocyclyl; R.sub.2 is selected from
hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted
or unsubstituted C.sub.2-6 alkenyl, substituted or unsubstituted
C.sub.2-6 alkynyl, substituted or unsubstituted cycloalkyl,
substituted or unsubstituted aryl and substituted or unsubstituted
heterocyclyl; R.sub.4 and R.sub.4' are independently selected from
hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted
or unsubstituted C.sub.2-6 alkenyl, substituted or unsubstituted
C.sub.2-6 alkynyl, --CHOR.sub.9 and --C(O)OR.sub.9; [0258] wherein
R.sub.9 is selected from hydrogen, substituted or unsubstituted
C.sub.1-9 alkyl, substituted or unsubstituted C.sub.2-9 alkenyl and
substituted or unsubstituted C.sub.2-9 alkynyl; R.sub.5 and
R.sub.5' are independently selected from hydrogen, substituted or
unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted
C.sub.2-6 alkenyl, substituted or unsubstituted C.sub.2-6 alkynyl,
substituted or unsubstituted cycloalkyl, substituted or
unsubstituted aryl, substituted or unsubstituted heterocyclyl,
--CHOR.sub.8 and --C(O)OR.sub.8; [0259] wherein R.sub.8 is selected
from hydrogen, substituted or unsubstituted C.sub.1-6 alkyl,
substituted or unsubstituted C.sub.2-6 alkenyl and substituted or
unsubstituted C.sub.2-6 alkynyl; alternatively R.sub.5 and R.sub.5'
taken together with the connecting C-atom may form a substituted or
unsubstituted cycloalkyl or a substituted or unsubstituted
heterocyclyl; optionally in form of one of the stereoisomers,
preferably enantiomers or diastereomers, a racemate or in form of a
mixture of at least two of the stereoisomers, preferably
enantiomers and/or diastereomers, in any mixing ratio, or a
corresponding salt thereof, or a corresponding solvate thereof.
[0260] In a further preferred embodiment of the invention according
to general Formula (I) the compound is a compound of Formula
(I.sup.4'),
##STR00041##
wherein R.sub.1 is
##STR00042##
m is 1, 2, 3, 4 or 5; p is 0 or 1; q is 0, 1 or 2; r is 0, 1 or 2;
R.sub.1' is selected from substituted or unsubstituted C.sub.1-6
alkyl, substituted or unsubstituted C.sub.2-6 alkenyl, substituted
or unsubstituted C.sub.2-6 alkynyl, substituted or unsubstituted
cycloalkyl, substituted or unsubstituted aryl and substituted or
unsubstituted heterocyclyl; R.sub.2 is selected from hydrogen,
substituted or unsubstituted C.sub.1-6 alkyl, substituted or
unsubstituted C.sub.2-6 alkenyl, substituted or unsubstituted
C.sub.2-4 alkynyl, substituted or unsubstituted cycloalkyl,
substituted or unsubstituted aryl and substituted or unsubstituted
heterocyclyl; R.sub.4 and R.sub.4' are independently selected from
hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted
or unsubstituted C.sub.2-6 alkenyl, substituted or unsubstituted
C.sub.2-6 alkynyl, --CHOR.sub.9 and --C(O)OR.sub.9; [0261] wherein
R.sub.9 is selected from hydrogen, substituted or unsubstituted
C.sub.1-9 alkyl, substituted or unsubstituted C.sub.2-9 alkenyl and
substituted or unsubstituted C.sub.2-9 alkynyl; R.sub.5 and
R.sub.5' are independently selected from hydrogen, substituted or
unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted
C.sub.2-6 alkenyl, substituted or unsubstituted C.sub.2-6 alkynyl,
substituted or unsubstituted cycloalkyl, substituted or
unsubstituted aryl, substituted or unsubstituted heterocyclyl,
--CHOR.sub.8 and --C(O)OR.sub.8; [0262] wherein R.sub.8 is selected
from hydrogen, substituted or unsubstituted C.sub.1-6 alkyl,
substituted or unsubstituted C.sub.2-6 alkenyl and substituted or
unsubstituted C.sub.2-6 alkynyl; alternatively R.sub.5 and R.sub.5'
taken together with the connecting C-atom may form a substituted or
unsubstituted cycloalkyl or a substituted or unsubstituted
heterocyclyl; optionally in form of one of the stereoisomers,
preferably enantiomers or diastereomers, a racemate or in form of a
mixture of at least two of the stereoisomers, preferably
enantiomers and/or diastereomers, in any mixing ratio, or a
corresponding salt thereof, or a corresponding solvate thereof.
[0263] In a further preferred embodiment of the invention according
to general Formula (I) the compound is a compound of Formula
(I.sup.5'),
##STR00043##
wherein m is 1, 2, 3, 4 or 5; p is 0 or 1; q is 0, 1 or 2; r is 0,
1 or 2; R.sub.1' is selected from substituted or unsubstituted
C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl,
substituted or unsubstituted C.sub.2-6 alkynyl, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted aryl and
substituted or unsubstituted heterocyclyl; R.sub.2 is selected from
hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted
or unsubstituted C.sub.2-6 alkenyl, substituted or unsubstituted
C.sub.2-6 alkynyl, substituted or unsubstituted cycloalkyl,
substituted or unsubstituted aryl and substituted or unsubstituted
heterocyclyl; R.sub.4 and R.sub.4' are independently selected from
hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted
or unsubstituted C.sub.2-6 alkenyl, substituted or unsubstituted
C.sub.2-6 alkynyl, --CHOR.sub.9 and --C(O)OR.sub.9; [0264] wherein
R is selected from hydrogen, substituted or unsubstituted C.sub.1-9
alkyl, substituted or unsubstituted C.sub.2-9 alkenyl and
substituted or unsubstituted C.sub.2-9 alkynyl; R.sub.5 and
R.sub.5' are independently selected from hydrogen, substituted or
unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted
C.sub.2-6 alkenyl, substituted or unsubstituted C.sub.2-6 alkynyl,
substituted or unsubstituted cycloalkyl, substituted or
unsubstituted aryl, substituted or unsubstituted heterocyclyl,
--CHOR.sub.8 and --C(O)OR.sub.8; [0265] wherein R is selected from
hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted
or unsubstituted C.sub.2-6 alkenyl and substituted or unsubstituted
C.sub.2-6 alkynyl; alternatively R.sub.5 and R.sub.5' taken
together with the connecting C-atom may form a substituted or
unsubstituted cycloalkyl or a substituted or unsubstituted
heterocyclyl; optionally in form of one of the stereoisomers,
preferably enantiomers or diastereomers, a racemate or in form of a
mixture of at least two of the stereoisomers, preferably
enantiomers and/or diastereomers, in any mixing ratio, or a
corresponding salt thereof, or a corresponding solvate thereof.
[0266] In a further preferred embodiment of the compound of Formula
(I.sup.5') the following proviso applies: [0267] q is not 1 when r
is 1.
[0268] In a preferred embodiment
R.sub.1 is a substituted or unsubstituted group selected from
methyl, ethyl, isopropyl, benzyl, benzoyl and phenyl, preferably an
unsubstituted group selected from methyl, ethyl, isopropyl, benzyl,
benzoyl and phenyl.
[0269] In a preferred embodiment
R.sub.1' is a substituted or unsubstituted group selected from
methyl, ethyl, isopropyl and phenyl, preferably an unsubstituted
group selected from methyl, ethyl, isopropyl and phenyl
[0270] In a preferred embodiment
R.sub.2 is a substituted or unsubstituted group selected from
isopropyl, isobutyl, tert-butyl, 2,2-dimethylpropyl and phenyl;
more preferably an unsubstituted group selected from isopropyl,
isobutyl, tert-butyl, 2,2-dimethylpropyl and phenyl.
[0271] In a preferred embodiment
R.sub.3 is hydrogen or substituted or unsubstituted methyl,
preferably hydrogen or unsubstituted methyl.
[0272] In a preferred embodiment
R.sub.3' is hydrogen or substituted or unsubstituted methyl,
preferably hydrogen or unsubstituted methyl.
[0273] In a preferred embodiment
R.sub.3 is hydrogen or substituted or unsubstituted methyl,
preferably unsubstituted methyl, while R.sub.3' is hydrogen or
substituted or unsubstituted methyl, preferably unsubstituted
methyl.
[0274] In a preferred embodiment
R.sub.3 is hydrogen, while R.sub.3' is substituted or unsubstituted
methyl, preferably unsubstituted methyl.
[0275] In a preferred embodiment
R.sub.3 is substituted or unsubstituted methyl, preferably
unsubstituted methyl, while R.sub.3' is hydrogen or substituted or
unsubstituted methyl, preferably unsubstituted methyl.
[0276] In a preferred embodiment
R.sub.3 is substituted or unsubstituted methyl, preferably
unsubstituted methyl, while R.sub.3' is hydrogen.
[0277] In a preferred embodiment
R.sub.3 and R.sub.3' are both substituted or unsubstituted methyl,
preferably R.sub.3 and R.sub.3' are both unsubstituted methyl
[0278] In a preferred embodiment
R.sub.3 and R.sub.3' taken together with the connecting C-atom form
a substituted or unsubstituted cyclopropyl; preferably a
substituted or unsubstituted C.sub.3-6 cyclopropyl; more preferably
unsubstituted cyclopropyl.
[0279] In a preferred embodiment
R.sub.4 and R.sub.4' are both hydrogen.
[0280] In a preferred embodiment
R.sub.5 and R.sub.5' are both hydrogen.
[0281] In a preferred embodiment
R.sub.6 and R.sub.6' are both hydrogen.
[0282] In a preferred embodiment
X is a bond.
[0283] In a preferred embodiment
X--O--.
[0284] In a preferred embodiment
X--O--, while m is 2.
[0285] In a preferred embodiment
Y is --CH.sub.2-- or --C(O)--.
[0286] In another preferred embodiment
n is 0.
[0287] In another preferred embodiment
n is 1.
[0288] In another preferred embodiment
m is 1 or 2.
[0289] In another preferred embodiment
m is 1.
[0290] In another preferred embodiment
m is 2.
[0291] In another preferred embodiment
p is 0 or 1.
[0292] In another preferred embodiment
p is 0.
[0293] In another preferred embodiment
q is 0 or 1.
[0294] In another preferred embodiment
r is 0 or 2.
[0295] In an particular embodiment
the halogen is fluorine or chlorine.
[0296] In a preferred further embodiment, the compounds of the
general Formula (I) are selected from
TABLE-US-00001 EX Structure Chemical name 1 ##STR00044##
12-Ethyl-7-isopentyl-4-oxa-7,12-diazadispiro[2.1.5.3]tridecan-
13-one 2 ##STR00045##
12-Ethyl-7-phenethyl-4-oxa-7,12-diazadispiro[2.1.5.3]tridecan-
13-one 3 ##STR00046## 13-ethyl-8-phenethyl-4-oxa-8,13-
diazadispiro[2.1.6.3]tetradecan-14-one 4 ##STR00047##
13-ethyl-8-isopentyl-4-oxa-8,13-
diazadispiro[2.1.6.3]tetradecan-14-one 5 ##STR00048##
7-benzyl-10-ethyl-4-oxa-7,10-diazadispiro[2.1.3.3]undecan- 11-one 6
##STR00049##
10-ethyl-7-isopentyl-4-oxa-7,10-diazadispiro[2.1.3.3]undecan-
11-one 7 ##STR00050## 7-phenethyl-12-phenyl-4-oxa-7,12-
diazadispiro[2.1.5.3]tridecan-13-one 8 ##STR00051##
7-isopentyl-12-phenyl-4-oxa-7,12-
diazadispiro[2.1.5.3]tridecan-13-one 9 ##STR00052##
8-phenethyl-13-phenyl-4-oxa-8,13-
diazadispiro[2.1.6.3]tetradecan-14-one 10 ##STR00053##
8-isopentyl-13-phenyl-4-oxa-8,13-
diazadispiro[2.1.6.3]tetradecan-14-one 11 ##STR00054##
7-Benzyl-12-ethyl-4-oxa-7,12-diazadispiro[2.1.5.3]tridecan-13- one
12 ##STR00055##
8-benzyl-13-ethyl-4-oxa-8,13-diazadispiro[2.1.6.3]tetradecan-
14-one 13 ##STR00056##
7-benzyl-10-ethyl-4-oxa-7,10-diazadispiro[2.1.3.3]undecan- 11-one
14 ##STR00057## 8-benzyl-13-phenyl-4-oxa-8,13-
diazadispiro[2.1.6.3]tetradecan-14-one 15 ##STR00058##
7-benzyl-12-phenyl-4-oxa-7,12-diazadispiro[2.1.5.3]tridecan- 13-one
16 ##STR00059## 13-Ethyl-8-phenethyl-4-oxa-8,13-
diazadispiro[2.1.6.3]tetradecane 17 ##STR00060##
7-benzyl-12-ethyl-4-oxa-7,12-diazadispiro[2.1.5.3]tridecane 18
##STR00061## 13-ethyl-8-phenethyl-4-oxa-8,13-
diazadispiro[2.1.6.3]tetradecane 19 ##STR00062##
7-phenethyl-12-phenyl-4-oxa-7,12- diazadispiro[2.1.5.3]tridecane 20
##STR00063## 7-isopentyl-12-phenyl-4-oxa-7,12-
diazadispiro[2.1.5.3]tridecane 21 ##STR00064##
8-benzyl-13-phenyl-4-oxa-8,13- diazadispiro[2.1.6.3]tetradecane 22
##STR00065## 8-phenethyl-13-phenyl-4-oxa-8,13-
diazadispiro[2.1.6.3]tetradecane
optionally in form of one of the stereoisomers, preferably
enantiomers or diastereomers, a racemate or in form of a mixture of
at least two of the stereoisomers, preferably enantiomers and/or
diastereomers, in any mixing ratio, or a corresponding salt
thereof, or a corresponding solvate thereof.
[0297] In a preferred further embodiment, the compounds of the
general Formula (I) are selected from
TABLE-US-00002 23 ##STR00066##
7-benzyl-12-phenyl-4-oxa-7,12-diazadispiro[2.1.5.3]tridecane 24
##STR00067##
(7-phenethyl-4-oxa-7,12-diazadispiro[2.1.5.3]tridecan-12-
yl)(phenyl)methanone 25 ##STR00068##
(7-isopentyl-4-oxa-7,12-diazadispiro[2.1.5.3]tridecan-12-
yl)(phenyl)methanone 26 ##STR00069##
(7-isobutyl-4-oxa-7,12-diazadispiro[2.1.5.3]tridecan-12-
yl)(phenyl)methanone 27 ##STR00070##
(8-phenethyl-4-oxa-8,13-diazadispiro[2.1.6.3]tetradecan-13-
yl)(phenyl)methanone 28 ##STR00071##
(8-isopentyl-4-oxa-8,13-diazadispiro[2.1.6.3]tetradecan-13-
yl)(phenyl)methanone 29 ##STR00072##
(8-isobutyl-4-oxa-8,13-diazadispiro[2.1.6.3]tetradecan-13-
yl)(phenyl)methanone 30 ##STR00073##
4-ethyl-2,2-dimethyl-9-phenethyl-1-oxa-4,9-
diazaspiro[5.6]dodecan-3-one 31 ##STR00074##
4-ethyl-9-isopentyl-2,2-dimethyl-1-oxa-4,9-
diazaspiro[5.6]dodecan-3-one 32 ##STR00075##
4-ethyl-9-isobutyl-2,2-dimethyl-1-oxa-4,9-
diazaspiro[5.6]dodecan-3-one 33 ##STR00076##
10-benzyl-7-phenethyl-4-oxa-7,10-
diazadispiro[2.1.3.3]undecan-11-one 34 ##STR00077##
(2,2-dimethyl-9-phenethyl-1-oxa-4,9-diazaspiro[5.6]dodecan-
4-yl)(phenyl)methanone 35 ##STR00078##
10-ethyl-7-(2-isopropoxyethyl)-4-oxa-7,10-
diazadispiro[2.1.3.3]undecan-11-one 36 ##STR00079##
(R)-8-ethyl-2-isopentyl-6-methyl-5-oxa-2,8-
diazaspiro[3.5]nonan-7-one 37 ##STR00080##
(S)-8-ethyl-2-isopentyl-6-methyl-5-oxa-2,8-
diazaspiro[3.5]nonan-7-one 38 ##STR00081##
(R)-8-ethyl-2-isobutyl-6-methyl-5-oxa-2,8-
diazaspiro[3.5]nonan-7-one 39 ##STR00082##
(S)-8-ethyl-2-isobutyl-6-methyl-5-oxa-2,8-
diazaspiro[3.5]nonan-7-one 40 ##STR00083##
(R)-2-isopentyl-8-isopropyl-6-methyl-5-oxa-2,8-
diazaspiro[3.5]nonan-7-one 41 ##STR00084##
(S)-2-isopentyl-8-isopropyl-6-methyl-5-oxa-2,8-
diazaspiro[3.5]nonan-7-one 42 ##STR00085##
(R)-2-isobutyl-8-isopropyl-6-methyl-5-oxa-2,8-
diazaspiro[3.5]nonan-7-one 43 ##STR00086##
(S)-2-isobutyl-8-isopropyl-6-methyl-5-oxa-2,8-
diazaspiro[3.5]nonan-7-one 44 ##STR00087##
(S)-2-(3,3-dimethylbutyl)-8-isopropyl-6-methyl-5-oxa-2,8-
diazaspiro[3.5]nonan-7-one 45 ##STR00088##
(R)-2-(3,3-dimethylbutyl)-8-isopropyl-6-methyl-5-oxa-2,8-
diazaspiro[3.5]nonan-7-one 46 ##STR00089##
(2R,6S)-4-ethyl-9-isopentyl-2-methyl-1-oxa-4,9-
diazaspiro[5.6]dodecan-3-one 47 ##STR00090##
(2R,6R)-4-ethyl-9-isopentyl-2-methyl-1-oxa-4,9-
diazaspiro[5.6]dodecan-3-one 48 ##STR00091##
(2S,6S)-4-ethyl-9-isopentyl-2-methyl-1-oxa-4,9-
diazaspiro[5.6]dodecan-3-one 49 ##STR00092##
(2S,6R)-4-ethyl-9-isopentyl-2-methyl-1-oxa-4,9-
diazaspiro[5.6]dodecan-3-one 50 ##STR00093##
(9-(2-isopropoxyethyl)-2,2-dimethyl-1-oxa-4,9-
diazaspiro[5.6]dodecan-4-yl)(phenyl)methanone 51 ##STR00094##
((2S,6R)-9-isopentyl-2-methyl-1-oxa-4,9-
diazaspiro[5.6]dodecan-4-yl)(phenyl)methanone 52 ##STR00095##
((2S,6S)-9-isopentyl-2-methyl-1-oxa-4,9-
diazaspiro[5.6]dodecan-4-yl)(phenyl)methanone 53 ##STR00096##
((2R,6R)-9-isopentyl-2-methyl-1-oxa-4,9-
diazaspiro[5.6]dodecan-4-yl)(phenyl)methanone 54 ##STR00097##
((2R,6S)-9-isopentyl-2-methyl-1-oxa-4,9-
diazaspiro[5.6]dodecan-4-yl)(phenyl)methanone 55 ##STR00098##
(7-benzyl-4-oxa-7,12-diazadispiro[2.1.5.3]tridecan-12-
yl)(phenyl)methanone 56 ##STR00099##
(8-benzyl-4-oxa-8,13-diazadispiro[2.1.6.3]tetradecan-13-
yl)(phenyl)methanone 57 ##STR00100##
9-benzyl-4-ethyl-2,2-dimethyl-1-oxa-4,9-
diazaspiro[5.6]dodecan-3-one 58 ##STR00101##
4-((4-ethyl-2,2-dimethyl-3-oxo-1-oxa-4,9-
diazaspiro[5.6]dodecan-9-yl)methyl)benzonitrile 59 ##STR00102##
(2R,6S)-9-benzyl-4-ethyl-2-methyl-1-oxa-4,9-
diazaspiro[5.6]dodecan-3-one 60 ##STR00103##
(2R,6R)-9-benzyl-4-ethyl-2-methyl-1-oxa-4,9-
diazaspiro[5.6]dodecan-3-one 61 ##STR00104##
(2S,6S)-9-benzyl-4-ethyl-2-methyl-1-oxa-4,9-
diazaspiro[5.6]dodecan-3-one 62 ##STR00105##
(2S,6R)-9-benzyl-4-ethyl-2-methyl-1-oxa-4,9-
diazaspiro[5.6]dodecan-3-one 63 ##STR00106##
(2R,6S)-4-ethyl-9-(4-fluorobenzyl)-2-methyl-1-oxa-4,9-
diazaspiro[5.6]dodecan-3-one 64 ##STR00107##
(2R,6R)-4-ethyl-9-(4-fluorobenzyl)-2-methyl-1-oxa-4,9-
diazaspiro[5.6]dodecan-3-one 65 ##STR00108##
(2S,6S)-4-ethyl-9-(4-fluorobenzyl)-2-methyl-1-oxa-4,9-
diazaspiro[5.6]dodecan-3-one 66 ##STR00109##
(2S,6R)-4-ethyl-9-(4-fluorobenzyl)-2-methyl-1-oxa-4,9-
diazaspiro[5.6]dodecan-3-one 67 ##STR00110##
4-(((2R,6S)-4-ethyl-2-methyl-3-oxo-1-oxa-4,9-
diazaspiro[5.6]dodecan-9-yl)methyl)benzonitrile 68 ##STR00111##
4-(((2R,6R)-4-ethyl-2-methyl-3-oxo-1-oxa-4,9-
diazaspiro[5.6]dodecan-9-yl)methyl)benzonitrile 69 ##STR00112##
4-(((2S,6S)-4-ethyl-2-methyl-3-oxo-1-oxa-4,9-
diazaspiro[5.6]dodecan-9-yl)methyl)benzonitrile 70 ##STR00113##
4-(((2S,6R)-4-ethyl-2-methyl-3-oxo-1-oxa-4,9-
diazaspiro[5.6]dodecan-9-yl)methyl)benzonitrile 71 ##STR00114##
8-benzyl-13-methyl-4-oxa-8,13-
diazadispiro[2.1.6.3]tetradecan-14-one 72 ##STR00115##
8-(4-fluorobenzyl)-13-methyl-4-oxa-8,13-
diazadispiro[2.1.6.3]tetradecan-14-one 73 ##STR00116##
4-((13-methyl-14-oxo-4-oxa-8,13-
diazadispiro[2.1.6.3]tetradecan-8-yl)methyl)benzonitrile 74
##STR00117## (S)-8-ethyl-6-methyl-2-neopentyl-5-oxa-2,8-
diazaspiro[3.5]nonan-7-one 75 ##STR00118##
(R)-8-ethyl-6-methyl-2-neopentyl-5-oxa-2,8-
diazaspiro[3.5]nonan-7-one 76 ##STR00119##
(S)-8-isopropyl-6-methyl-2-neopentyl-5-oxa-2,8-
diazaspiro[3.5]nonan-7-one 77 ##STR00120##
(R)-8-isopropyl-6-methyl-2-neopentyl-5-oxa-2,8-
diazaspiro[3.5]nonan-7-one 78 ##STR00121##
7,12-dibenzyl-4-oxa-7,12-diazadispiro[2.1.5.3]tridecane(*) 79
##STR00122## 12-benzyl-7-phenethyl-4-oxa-7,12-
diazadispiro[2.1.5.3]tridecane(*) 80 ##STR00123##
12-benzyl-7-isopentyl-4-oxa-7,12- diazadispiro[2.1.5.3]tridecane(*)
81 ##STR00124## 12-benzyl-7-isobutyl-4-oxa-7,12-
diazadispiro[2.1.5.3]tridecane(*) 82 ##STR00125##
8,13-dibenzyl-4-oxa-8,13-diazadispiro[2.1.6.3]tetradecane(*) 83
##STR00126## 13-benzyl-8-phenethyl-4-oxa-8,13-
diazadispiro[2.1.6.3]tetradecane(*) 84 ##STR00127##
13-benzyl-8-isopentyl-4-oxa-8,13-
diazadispiro[2.1.6.3]tetradecane(*) 85 ##STR00128##
13-benzyl-8-isobutyl-4-oxa-8,13-
diazadispiro[2.1.6.3]tetradecane(*) 86 ##STR00129##
9-benzyl-4-ethyl-2,2-dimethyl-1-oxa-4,9- diazaspiro[5.6]dodecane 87
##STR00130## 4-ethyl-2,2-dimethyl-9-phenethyl-1-oxa-4,9-
diazaspiro[5.6]dodecane 88 ##STR00131##
4-ethyl-9-isopentyl-2,2-dimethyl-1-oxa-4,9- diazaspiro[5.6]dodecane
89 ##STR00132## 4-ethyl-9-isobutyl-2,2-dimethyl-1-oxa-4,9-
diazaspiro[5.6]dodecane 90 ##STR00133##
10-benzyl-7-phenethyl-4-oxa-7,10- diazadispiro[2.1.3.3]undecane 91
##STR00134##
(7-Phenethyl-4-oxa-7,10-diazadispiro[2.1.3.3]undecan-10-
yl)(phenyl)methanone 92 ##STR00135##
(R)-8-benzyl-13-ethyl-4-oxa-8,13-
diazadispiro[2.1.6.3]tetradecan-14-one 93 ##STR00136##
(S)-8-benzyl-13-ethyl-4-oxa-8,13-
diazadispiro[2.1.6.3]tetradecan-14-one 94 ##STR00137##
(R)-(2,2-dimethyl-9-phenethyl-1-oxa-4,9-
diazaspiro[5.6]dodecan-4-yl)(phenyl)methanone 95 ##STR00138##
(S)-(2,2-dimethyl-9-phenethyl-1-oxa-4,9-
diazaspiro[5.6]dodecan-4-yl)(phenyl)methanone 96 ##STR00139##
(R)-(8-isopentyl-4-oxa-8,13-diazadispiro[2.1.6.3]tetradecan-
13-yl)(phenyl)methanone 97 ##STR00140##
(S)-(8-isopentyl-4-oxa-8,13-diazadispiro[2.1.6.3]tetradecan-
13-yl)(phenyl)methanone
optionally in form of one of the stereoisomers, preferably
enantiomers or diastereomers, a racemate or in form of a mixture of
at least two of the stereoisomers, preferably enantiomers and/or
diastereomers, in any mixing ratio, or a corresponding salt
thereof, or a corresponding solvate thereof.
[0298] In a preferred further embodiment, the compounds of the
general Formula (I) are selected from
TABLE-US-00003 23 ##STR00141##
7-benzyl-12-phenyl-4-oxa-7,12-diazadispiro[2.1.5.3]tridecane 24
##STR00142##
(7-phenethyl-4-oxa-7,12-diazadispiro[2.1.5.3]tridecan-12-
yl)(phenyl)methanone 25 ##STR00143##
(7-isopentyl-4-oxa-7,12-diazadispiro[2.1.5.3]tridecan-12-
yl)(phenyl)methanone 26 ##STR00144##
(7-isobutyl-4-oxa-7,12-diazadispiro[2.1.5.3]tridecan-12-
yl)(phenyl)methanone 27 ##STR00145##
(8-phenethyl-4-oxa-8,13-diazadispiro[2.1.6.3]tetradecan-13-
yl)(phenyl)methanone 28 ##STR00146##
(8-isopentyl-4-oxa-8,13-diazadispiro[2.1.6.3]tetradecan-13-
yl)(phenyl)methanone 29 ##STR00147##
(8-isobutyl-4-oxa-8,13-diazadispiro[2.1.6.3]tetradecan-13-
yl)(phenyl)methanone 30 ##STR00148##
4-ethyl-2,2-dimethyl-9-phenethyl-1-oxa-4,9-
diazaspiro[5.6]dodecan-3-one 31 ##STR00149##
4-ethyl-9-isopentyl-2,2-dimethyl-1-oxa-4,9-
diazaspiro[5.6]dodecan-3-one 32 ##STR00150##
4-ethyl-9-isobutyl-2,2-dimethyl-1-oxa-4,9-
diazaspiro[5.6]dodecan-3-one 33 ##STR00151##
10-benzyl-7-phenethyl-4-oxa-7,10-
diazadispiro[2.1.3.3]undecan-11-one 34 ##STR00152##
(2,2-dimethyl-9-phenethyl-1-oxa-4,9-diazaspiro[5.6]dodecan-
4-yl)(phenyl)methanone 35 ##STR00153##
10-ethyl-7-(2-isopropoxyethyl)-4-oxa-7,10-
diazadispiro[2.1.3.3]undecan-11-one 36 ##STR00154##
(R)-8-ethyl-2-isopentyl-6-methyl-5-oxa-2,8-
diazaspiro[3.5]nonan-7-one 37 ##STR00155##
(S)-8-ethyl-2-isopentyl-6-methyl-5-oxa-2,8-
diazaspiro[3.5]nonan-7-one 38 ##STR00156##
(R)-8-ethyl-2-isobutyl-6-methyl-5-oxa-2,8-
diazaspiro[3.5]nonan-7-one 39 ##STR00157##
(S)-8-ethyl-2-isobutyl-6-methyl-5-oxa-2,8-
diazaspiro[3.5]nonan-7-one 40 ##STR00158##
(R)-2-isopentyl-8-isopropyl-6-methyl-5-oxa-2,8-
diazaspiro[3.5]nonan-7-one 41 ##STR00159##
(S)-2-isopentyl-8-isopropyl-6-methyl-5-oxa-2,8-
diazaspiro[3.5]nonan-7-one 42 ##STR00160##
(R)-2-isobutyl-8-isopropyl-6-methyl-5-oxa-2,8-
diazaspiro[3.5]nonan-7-one 43 ##STR00161##
(S)-2-isobutyl-8-isopropyl-6-methyl-5-oxa-2,8-
diazaspiro[3.5]nonan-7-one 44 ##STR00162##
(S)-2-(3,3-dimethylbutyl)-8-isopropyl-6-methyl-5-oxa-2,8-
diazaspiro[3.5]nonan-7-one 45 ##STR00163##
(R)-2-(3,3-dimethylbutyl)-8-isopropyl-6-methyl-5-oxa-2,8-
diazaspiro[3.5]nonan-7-one 46 ##STR00164##
(2R,6S)-4-ethyl-9-isopentyl-2-methyl-1-oxa-4,9-
diazaspiro[5.6]dodecan-3-one 47 ##STR00165##
(2R,6R)-4-ethyl-9-isopentyl-2-methyl-1-oxa-4,9-
diazaspiro[5.6]dodecan-3-one 48 ##STR00166##
(2S,6S)-4-ethyl-9-isopentyl-2-methyl-1-oxa-4,9-
diazaspiro[5.6]dodecan-3-one 49 ##STR00167##
(2S,6R)-4-ethyl-9-isopentyl-2-methyl-1-oxa-4,9-
diazaspiro[5.6]dodecan-3-one 50 ##STR00168##
(9-(2-isopropoxyethyl)-2,2-dimethyl-1-oxa-4,9-
diazaspiro[5.6]dodecan-4-yl)(phenyl)methanone 55 ##STR00169##
(7-benzyl-4-oxa-7,12-diazadispiro[2.1.5.3]tridecan-12-
yl)(phenyl)methanone 56 ##STR00170##
(8-benzyl-4-oxa-8,13-diazadispiro[2.1.6.3]tetradecan-13-
yl)(phenyl)methanone 57 ##STR00171##
9-benzyl-4-ethyl-2,2-dimethyl-1-oxa-4,9-
diazaspiro[5.6]dodecan-3-one 58 ##STR00172##
4-((4-ethyl-2,2-dimethyl-3-oxo-1-oxa-4,9-
diazaspiro[5.6]dodecan-9-yl)methyl)benzonitrile 59 ##STR00173##
(2R,6S)-9-benzyl-4-ethyl-2-methyl-1-oxa-4,9-
diazaspiro[5.6]dodecan-3-one 60 ##STR00174##
(2R,6R)-9-benzyl-4-ethyl-2-methyl-1-oxa-4,9-
diazaspiro[5.6]dodecan-3-one 61 ##STR00175##
(2S,6S)-9-benzyl-4-ethyl-2-methyl-1-oxa-4,9-
diazaspiro[5.6]dodecan-3-one 62 ##STR00176##
(2S,6R)-9-benzyl-4-ethyl-2-methyl-1-oxa-4,9-
diazaspiro[5.6]dodecan-3-one 63 ##STR00177##
(2R,6S)-4-ethyl-9-(4-fluorobenzyl)-2-methyl-1-oxa-4,9-
diazaspiro[5.6]dodecan-3-one 64 ##STR00178##
(2R,6R)-4-ethyl-9-(4-fluorobenzyl)-2-methyl-1-oxa-4,9-
diazaspiro[5.6]dodecan-3-one 65 ##STR00179##
(2S,6S)-4-ethyl-9-(4-fluorobenzyl)-2-methyl-1-oxa-4,9-
diazaspiro[5.6]dodecan-3-one 66 ##STR00180##
(2S,6R)-4-ethyl-9-(4-fluorobenzyl)-2-methyl-1-oxa-4,9-
diazaspiro[5.6]dodecan-3-one 67 ##STR00181##
4-(((2R,6S)-4-ethyl-2-methyl-3-oxo-1-oxa-4,9-
diazaspiro[5.6]dodecan-9-yl)methyl)benzonitrile 68 ##STR00182##
4-(((2R,6R)-4-ethyl-2-methyl-3-oxo-1-oxa-4,9-
diazaspiro[5.6]dodecan-9-yl)methyl)benzonitrile 69 ##STR00183##
4-(((2S,6S)-4-ethyl-2-methyl-3-oxo-1-oxa-4,9-
diazaspiro[5.6]dodecan-9-yl)methyl)benzonitrile 70 ##STR00184##
4-(((2S,6R)-4-ethyl-2-methyl-3-oxo-1-oxa-4,9-
diazaspiro[5.6]dodecan-9-yl)methyl)benzonitrile 71 ##STR00185##
8-benzyl-13-methyl-4-oxa-8,13-
diazadispiro[2.1.6.3]tetradecan-14-one 72 ##STR00186##
8-(4-fluorobenzyl)-13-methyl-4-oxa-8,13-
diazadispiro[2.1.6.3]tetradecan-14-one 73 ##STR00187##
4-((13-methyl-14-oxo-4-oxa-8,13-
diazadispiro[2.1.6.3]tetradecan-8-yl)methyl)benzonitrile 74
##STR00188## (S)-8-ethyl-6-methyl-2-neopentyl-5-oxa-2,8-
diazaspiro[3.5]nonan-7-one 75 ##STR00189##
(R)-8-ethyl-6-methyl-2-neopentyl-5-oxa-2,8-
diazaspiro[3.5]nonan-7-one 76 ##STR00190##
(S)-8-isopropyl-6-methyl-2-neopentyl-5-oxa-2,8-
diazaspiro[3.5]nonan-7-one 77 ##STR00191##
(R)-8-isopropyl-6-methyl-2-neopentyl-5-oxa-2,8-
diazaspiro[3.5]nonan-7-one 78 ##STR00192##
7,12-dibenzyl-4-oxa-7,12-diazadispiro[2.1.5.3]tridecane(*) 79
##STR00193## 12-benzyl-7-phenethyl-4-oxa-7,12-
diazadispiro[2.1.5.3]tridecane(*) 80 ##STR00194##
12-benzyl-7-isopentyl-4-oxa-7,12- diazadispiro[2.1.5.3]tridecane(*)
81 ##STR00195## 12-benzyl-7-isobutyl-4-oxa-7,12-
diazadispiro[2.1.5.3]tridecane(*) 82 ##STR00196##
8,13-dibenzyl-4-oxa-8,13-diazadispiro[2.1.6.3]tetradecane(*) 83
##STR00197## 13-benzyl-8-phenethyl-4-oxa-8,13-
diazadispiro[2.1.6.3]tetradecane(*) 84 ##STR00198##
13-benzyl-8-isopentyl-4-oxa-8,13-
diazadispiro[2.1.6.3]tetradecane(*) 85 ##STR00199##
13-benzyl-8-isobutyl-4-oxa-8,13-
diazadispiro[2.1.6.3]tetradecane(*) 86 ##STR00200##
9-benzyl-4-ethyl-2,2-dimethyl-1-oxa-4,9- diazaspiro[5.6]dodecane 87
##STR00201## 4-ethyl-2,2-dimethyl-9-phenethyl-1-oxa-4,9-
diazaspiro[5.6]dodecane 88 ##STR00202##
4-ethyl-9-isopentyl-2,2-dimethyl-1-oxa-4,9- diazaspiro[5.6]dodecane
89 ##STR00203## 4-ethyl-9-isobutyl-2,2-dimethyl-1-oxa-4,9-
diazaspiro[5.6]dodecane 90 ##STR00204##
10-benzyl-7-phenethyl-4-oxa-7,10- diazadispiro[2.1.3.3]undecane 91
##STR00205##
(7-Phenethyl-4-oxa-7,10-diazadispiro[2.1.3.3]undecan-10-
yl)(phenyl)methanone 92 ##STR00206##
(R)-8-benzyl-13-ethyl-4-oxa-8,13-
diazadispiro[2.1.6.3]tetradecan-14-one 93 ##STR00207##
(S)-8-benzyl-13-ethyl-4-oxa-8,13-
diazadispiro[2.1.6.3]tetradecan-14-one 94 ##STR00208##
(R)-(2,2-dimethyl-9-phenethyl-1-oxa-4,9-
diazaspiro[5.6]dodecan-4-yl)(phenyl)methanone 95 ##STR00209##
(S)-(2,2-dimethyl-9-phenethyl-1-oxa-4,9-
diazaspiro[5.6]dodecan-4-yl)(phenyl)methanone
optionally in form of one of the stereoisomers, preferably
enantiomers or diastereomers, a racemate or in form of a mixture of
at least two of the stereoisomers, preferably enantiomers and/or
diastereomers, in any mixing ratio, or a corresponding salt
thereof, or a corresponding solvate thereof.
[0299] In a preferred further embodiment, the compounds of the
general Formula (I) are selected from
TABLE-US-00004 51 ##STR00210## ((2S,6R)-9-isopentyl-2-
methyl-1-oxa-4,9- diazaspiro[5.6]dodecan- 4-yl)(phenyl)methanone 52
##STR00211## ((2S,6S)-9-isopentyl-2- methyl-1-oxa-4,9-
diazaspiro[5.6]dodecan- 4-yl)(phenyl)methanone 53 ##STR00212##
((2R,6R)-9-isopentyl-2- methyl-1-oxa-4,9- diazaspiro[5.6]dodecan-
4-yl)(phenyl)methanone 54 ##STR00213## ((2R,6S)-9-isopentyl-2-
methyl-1-oxa-4,9- diazaspiro[5.6]dodecan- 4-yl)(phenyl)methanone 96
##STR00214## (R)-(8-isopentyl-4-oxa-8,13-
diazadispiro[2.1.6.3]tetradecan- 13-yl)(phenyl)methanone 97
##STR00215## (S)-(8-isopentyl-4-oxa-8,13-
diazadispiro[2.1.6.3]tetradecan- 13-yl)(phenyl)methanone
optionally in form of one of the stereoisomers, preferably
enantiomers or diastereomers, a racemate or in form of a mixture of
at least two of the stereoisomers, preferably enantiomers and/or
diastereomers, in any mixing ratio, or a corresponding salt
thereof, or a corresponding solvate thereof.
[0300] In a preferred embodiment of the compound according to the
invention of general Formula (I),
R.sub.1' is selected from substituted or unsubstituted C.sub.1-6
alkyl, substituted or unsubstituted C.sub.2-6 alkenyl, substituted
or unsubstituted C.sub.2-6 alkynyl, substituted or unsubstituted
cycloalkyl, substituted or unsubstituted aryl and substituted or
unsubstituted heterocyclyl; [0301] wherein said cycloalkyl, aryl or
heterocyclyl in R.sub.1' if substituted, is substituted with one or
more substituent/s selected from halogen, --R.sub.11, --OR.sub.11,
--NO.sub.2, --NR.sub.11R.sub.11''', NR.sub.11C(O)R.sub.11',
--NR.sub.11S(O).sub.2R.sub.11', --S(O).sub.2NR.sub.11R.sub.11',
--NR.sub.11C(O)NR.sub.11'R.sub.11'', --SR.sub.11, --S(O)R.sub.11,
S(O).sub.2R.sub.11, --CN, haloalkyl, haloalkoxy, --C(O)OR.sub.11,
--C(O)NR.sub.11R.sub.11', --OCH.sub.2CH.sub.2OH,
--NR.sub.11S(O).sub.2NR.sub.11'R.sub.11'' and
C(CH.sub.3).sub.2OR.sub.11; additionally, the cycloalkyl or
non-aromatic heterocyclyl in R.sub.1', if substituted, may also be
substituted with
##STR00216##
[0301] or .dbd.O;
[0302] wherein the alkyl, alkenyl or alkynyl in R.sub.1', if
substituted, is substituted with one or more substituent/s selected
from --OR.sub.11, halogen, --CN, haloalkyl, haloalkoxy and
--NR.sub.11R.sub.11'''; wherein R.sub.11, R.sub.11' and R.sub.11''
are independently selected from hydrogen, unsubstituted C.sub.1-6
alkyl, unsubstituted C.sub.2-6 alkenyl and unsubstituted C.sub.2-6
alkynyl; and wherein R.sub.11''' is selected from hydrogen,
unsubstituted C.sub.1-6 alkyl, unsubstituted C.sub.2-6 alkenyl,
unsubstituted C.sub.2-6 alkynyl and -Boc; optionally in form of one
of the stereoisomers, preferably enantiomers or diastereomers, a
racemate or in form of a mixture of at least two of the
stereoisomers, preferably enantiomers and/or diastereomers, in any
mixing ratio, or a corresponding salt thereof, or a corresponding
solvate thereof.
[0303] In another embodiment of the invention the compound of
general Formula (I),
R.sub.2 is selected from hydrogen, substituted or unsubstituted
C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl,
substituted or unsubstituted C.sub.2-6 alkynyl, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted aryl and
substituted or unsubstituted heterocyclyl, [0304] wherein said
cycloalkyl, aryl or heterocyclyl in R.sub.2, if substituted, is
substituted with one or more substituent/s selected from halogen,
--R.sub.12, --OR.sub.12, --NO.sub.2, --NR.sub.12R.sub.12''',
NR.sub.12C(O)R.sub.12', --NR.sub.12S(O).sub.2R.sub.12',
--S(O).sub.2NR.sub.12R.sub.12',
--NR.sub.12C(O)NR.sub.12'R.sub.12'', --SR.sub.12, --S(O)R.sub.12,
S(O).sub.2R.sub.12, --CN, haloalkyl, haloalkoxy, --C(O)OR.sub.12,
--C(O)NR.sub.12R.sub.12', --OCH.sub.2CH.sub.2OH,
--NR.sub.12S(O).sub.2NR.sub.12'R.sub.12'' and
C(CH.sub.3).sub.2OR.sub.12; [0305] additionally, the cycloalkyl or
non-aromatic heterocyclyl in R.sub.2, if substituted, may also be
substituted with
##STR00217##
[0305] or .dbd.O;
[0306] wherein the alkyl, alkenyl or alkynyl in R.sub.2, if
substituted, is substituted with one or more substituent/s selected
from --OR.sub.12, halogen, --CN, haloalkyl, haloalkoxy and
--NR.sub.12R.sub.12'''; [0307] wherein R.sub.12, R.sub.12' and
R.sub.12'' are independently selected from hydrogen, unsubstituted
C.sub.1-6 alkyl, unsubstituted C.sub.2-6 alkenyl and unsubstituted
C.sub.2-6 alkynyl; [0308] and wherein R.sub.12''' is selected from
hydrogen, unsubstituted C.sub.1-6 alkyl, unsubstituted C.sub.2-6
alkenyl, unsubstituted C.sub.2-6 alkynyl and -Boc; optionally in
form of one of the stereoisomers, preferably enantiomers or
diastereomers, a racemate or in form of a mixture of at least two
of the stereoisomers, preferably enantiomers and/or diastereomers,
in any mixing ratio, or a corresponding salt thereof, or a
corresponding solvate thereof.
[0309] In another embodiment of the invention the compound of
general Formula (I),
the alkyl, alkenyl or alkynyl, other than those defined in R.sub.1'
or R.sub.2, if substituted, is substituted with one or more
substituent/s selected from --OR.sub.13, halogen, --CN, haloalkyl,
haloalkoxy and --NR.sub.13R.sub.13'''; [0310] wherein R.sub.13, are
independently selected from hydrogen, unsubstituted C.sub.1-6
alkyl, unsubstituted C.sub.2-6 alkenyl, and unsubstituted C.sub.2-6
alkynyl; [0311] R.sub.13''' is selected from hydrogen,
unsubstituted C.sub.1-6 alkyl, unsubstituted C.sub.2-6 alkenyl,
unsubstituted C.sub.2-6 alkynyl and -Boc; optionally in form of one
of the stereoisomers, preferably enantiomers or diastereomers, a
racemate or in form of a mixture of at least two of the
stereoisomers, preferably enantiomers and/or diastereomers, in any
mixing ratio, or a corresponding salt thereof, or a corresponding
solvate thereof.
[0312] In another embodiment of the invention the compound of
general Formula (I),
the aryl, heterocyclyl or cycloalkyl other than those defined in
R.sub.1' or R.sub.2, if substituted, is substituted with one or
more substituent/s selected from halogen, --R.sub.14, --OR.sub.14,
--NO.sub.2, --NR.sub.14R.sub.14''', NR.sub.14C(O)R.sub.14',
--NR.sub.14S(O).sub.2R.sub.14', --S(O).sub.2NR.sub.14R.sub.14',
--NR.sub.14C(O)NR.sub.14'R.sub.14'', --SR.sub.14, --S(O)R.sub.14,
S(O).sub.2R.sub.14, --CN, haloalkyl, haloalkoxy, --C(O)OR.sub.14,
--C(O)NR.sub.14R.sub.14', --OCH.sub.2CH.sub.2OH,
--NR.sub.14S(O).sub.2NR.sub.14'R.sub.14'' and
C(CH.sub.3).sub.2OR.sub.14; additionally, wherein cycloalkyl or
non-aromatic heterocyclyl, other than those defined in R.sub.1' or
R.sub.2, if substituted, may also be substituted with
##STR00218##
or .dbd.O;
[0313] wherein R.sub.14, R.sub.14' and R.sub.14'' are independently
selected from hydrogen, unsubstituted C.sub.1-6 alkyl,
unsubstituted C.sub.2-6 alkenyl, unsubstituted C.sub.2-6 alkynyl,
unsubstituted aryl, unsubstituted cycloalkyl and unsubstituted
heterocyclyl; [0314] and wherein R.sub.14''' is selected from
hydrogen, unsubstituted C.sub.1-6 alkyl, unsubstituted C.sub.2-6
alkenyl, unsubstituted C.sub.2-6 alkynyl and -Boc; optionally in
form of one of the stereoisomers, preferably enantiomers or
diastereomers, a racemate or in form of a mixture of at least two
of the stereoisomers, preferably enantiomers and/or diastereomers,
in any mixing ratio, or a corresponding salt thereof, or a
corresponding solvate thereof.
[0315] In a preferred embodiment of the compound according to the
invention of general Formula (I) and in relation to R.sub.1' of any
of the embodiments of the present invention, [0316] the cycloalkyl,
aryl or heterocyclyl in R.sub.1' if substituted, is substituted
with one or more substituent/s selected from halogen, --R.sub.11,
--OR.sub.11, --NO.sub.2, --NR.sub.11R.sub.11''',
NR.sub.11C(O)R.sub.11', --NR.sub.11S(O).sub.2R.sub.11',
--S(O).sub.2NR.sub.11R.sub.11',
--NR.sub.11C(O)NR.sub.11'R.sub.11'', --SR.sub.11, --S(O)R.sub.11,
S(O).sub.2R.sub.11, --CN, haloalkyl, haloalkoxy, --C(O)OR.sub.11,
--C(O)NR.sub.11R.sub.11', --OCH.sub.2CH.sub.2OH,
--NR.sub.11S(O).sub.2NR.sub.11'R.sub.11'' and
C(CH.sub.3).sub.2OR.sub.11; optionally in form of one of the
stereoisomers, preferably enantiomers or diastereomers, a racemate
or in form of a mixture of at least two of the stereoisomers,
preferably enantiomers and/or diastereomers, in any mixing ratio,
or a corresponding salt thereof, or a corresponding solvate
thereof.
[0317] In a preferred embodiment of the compound according to the
invention of general Formula (I) and in relation to R.sub.1 of any
of the embodiments of the present invention, [0318] the cycloalkyl
or non-aromatic heterocyclyl in R.sub.1', if substituted, may also
be substituted with
##STR00219##
[0318] or .dbd.O;
[0319] optionally in form of one of the stereoisomers, preferably
enantiomers or diastereomers, a racemate or in form of a mixture of
at least two of the stereoisomers, preferably enantiomers and/or
diastereomers, in any mixing ratio, or a corresponding salt
thereof, or a corresponding solvate thereof.
[0320] In a preferred embodiment of the compound according to the
invention of general Formula (I) and in relation to R.sub.1, of any
of the embodiments of the present invention, [0321] the alkyl,
alkenyl or alkynyl in R.sub.1', if substituted, is substituted with
one or more substituent/s selected from --OR.sub.11, halogen, --CN,
haloalkyl, haloalkoxy and --NR.sub.11R.sub.11'''; optionally in
form of one of the stereoisomers, preferably enantiomers or
diastereomers, a racemate or in form of a mixture of at least two
of the stereoisomers, preferably enantiomers and/or diastereomers,
in any mixing ratio, or a corresponding salt thereof, or a
corresponding solvate thereof.
[0322] In a preferred embodiment of the compound according to the
invention of general Formula (I) and in relation to R.sub.2 of any
of the embodiments of the present invention, [0323] the cycloalkyl,
aryl or heterocyclyl in R.sub.2, if substituted, is substituted
with one or more substituent/s selected from halogen, --R.sub.12,
--OR.sub.12, --NO.sub.2, --NR.sub.12R.sub.12''',
NR.sub.12C(O)R.sub.12', --NR.sub.12S(O).sub.2R.sub.12',
--S(O).sub.2NR.sub.12R.sub.12',
--NR.sub.12C(O)NR.sub.12'R.sub.12'', --SR.sub.12, --S(O)R.sub.12,
S(O).sub.2R.sub.12, --CN, haloalkyl, haloalkoxy, --C(O)OR.sub.12,
--C(O)NR.sub.12R.sub.12', --OCH.sub.2CH.sub.2OH,
--NR.sub.12S(O).sub.2NR.sub.12'R.sub.12'' and
C(CH.sub.3).sub.2OR.sub.12; optionally in form of one of the
stereoisomers, preferably enantiomers or diastereomers, a racemate
or in form of a mixture of at least two of the stereoisomers,
preferably enantiomers and/or diastereomers, in any mixing ratio,
or a corresponding salt thereof, or a corresponding solvate
thereof.
[0324] In a preferred embodiment of the compound according to the
invention of general Formula (I) and in relation to R.sub.2 of any
of the embodiments of the present invention,
the cycloalkyl or non-aromatic heterocyclyl in R.sub.2, if
substituted, may also be substituted with
##STR00220##
or .dbd.O;
[0325] optionally in form of one of the stereoisomers, preferably
enantiomers or diastereomers, a racemate or in form of a mixture of
at least two of the stereoisomers, preferably enantiomers and/or
diastereomers, in any mixing ratio, or a corresponding salt
thereof, or a corresponding solvate thereof.
[0326] In a preferred embodiment of the compound according to the
invention of general Formula (I) and in relation to R.sub.2 of any
of the embodiments of the present invention,
the alkyl, alkenyl or alkynyl in R.sub.2, if substituted, is
substituted with one or more substituent/s selected from
--OR.sub.12, halogen, --CN, haloalkyl, haloalkoxy and
--NR.sub.12R.sub.12'''; optionally in form of one of the
stereoisomers, preferably enantiomers or diastereomers, a racemate
or in form of a mixture of at least two of the stereoisomers,
preferably enantiomers and/or diastereomers, in any mixing ratio,
or a corresponding salt thereof, or a corresponding solvate
thereof.
[0327] In a preferred embodiment of the compound according to the
invention of general Formula (I) and in relation to alkyls other
than those defined in R.sub.1' or R.sub.2 of any of the embodiments
of the present invention,
the alkyl, alkenyl or alkynyl, other than those defined in R.sub.1'
or R.sub.2, if substituted, is substituted with one or more
substituents selected from --OR.sub.13, halogen, --CN, haloalkyl,
haloalkoxy and --NR.sub.13R.sub.13'''; optionally in form of one of
the stereoisomers, preferably enantiomers or diastereomers, a
racemate or in form of a mixture of at least two of the
stereoisomers, preferably enantiomers and/or diastereomers, in any
mixing ratio, or a corresponding salt thereof, or a corresponding
solvate thereof.
[0328] In a preferred embodiment of the compound according to the
invention of general Formula (I) and in relation to the cycloalkyl,
aryl or heterocyclyl other than those defined in R.sub.1' or
R.sub.2 of any of the embodiments of the present invention,
the aryl, heterocyclyl or cycloalkyl other than those defined in
R.sub.1' or R.sub.2, if substituted, is substituted with one or
more substituent/s selected from halogen, --R.sub.14, --OR.sub.14,
--NO.sub.2, --NR.sub.14R.sub.14''', NR.sub.14C(O)R.sub.14',
--NR.sub.14S(O).sub.2R.sub.14', --S(O).sub.2NR.sub.14R.sub.14',
--NR.sub.14C(O)NR.sub.14'R.sub.14'', --SR.sub.14, --S(O)R.sub.14,
S(O).sub.2R.sub.14, --CN, haloalkyl, haloalkoxy, --C(O)OR.sub.14,
--C(O)NR.sub.14R.sub.14', --OCH.sub.2CH.sub.2OH,
--NR.sub.14S(O).sub.2NR.sub.14'R.sub.14'' and
C(CH.sub.3).sub.2OR.sub.14; optionally in form of one of the
stereoisomers, preferably enantiomers or diastereomers, a racemate
or in form of a mixture of at least two of the stereoisomers,
preferably enantiomers and/or diastereomers, in any mixing ratio,
or a corresponding salt thereof, or a corresponding solvate
thereof.
[0329] In a preferred embodiment of the compound according to the
invention of general Formula (I) and in relation to to the
cycloalkyl, aryl or heterocyclyl other than those defined in
R.sub.1' or R.sub.2 of any of the embodiments of the present
invention,
the cycloalkyl or non-aromatic heterocyclyl, other than those
defined in R.sub.1' or R.sub.2, if substituted, may also be
substituted with
##STR00221##
or .dbd.O;
[0330] optionally in form of one of the stereoisomers, preferably
enantiomers or diastereomers, a racemate or in form of a mixture of
at least two of the stereoisomers, preferably enantiomers and/or
diastereomers, in any mixing ratio, or a corresponding salt
thereof, or a corresponding solvate thereof.
[0331] In an embodiment of the compound according to the invention
of general Formula (I),
the halogen is fluorine, chlorine, iodine or bromine, preferably
fluorine or chlorine; optionally in form of one of the
stereoisomers, preferably enantiomers or diastereomers, a racemate
or in form of a mixture of at least two of the stereoisomers,
preferably enantiomers and/or diastereomers, in any mixing ratio,
or a corresponding salt thereof, or a corresponding solvate
thereof.
[0332] In an embodiment of the compound according to the invention
of general Formula (I),
the haloalkyl is --CF.sub.3; optionally in form of one of the
stereoisomers, preferably enantiomers or diastereomers, a racemate
or in form of a mixture of at least two of the stereoisomers,
preferably enantiomers and/or diastereomers, in any mixing ratio,
or a corresponding salt thereof, or a corresponding solvate
thereof.
[0333] In another embodiment of the compound according to the
invention of general Formula (I),
the haloalkoxy is --OCF.sub.3; optionally in form of one of the
stereoisomers, preferably enantiomers or diastereomers, a racemate
or in form of a mixture of at least two of the stereoisomers,
preferably enantiomers and/or diastereomers, in any mixing ratio,
or a corresponding salt thereof, or a corresponding solvate
thereof.
[0334] As this invention is aimed at providing a compound or a
chemically related series of compounds which act as ligands of the
ca receptor it is a very preferred embodiment in which the
compounds are selected which act as ligands of the or receptor and
especially compounds which have a binding expressed as K which is
preferably <1000 nM, more preferably <500 nM, even more
preferably <100 nM.
[0335] In the following the phrase "compound of the invention" is
used. This is to be understood as any compound according to the
invention as described above according to general Formula (I),
(I'), (I.sup.2'), (I.sup.3'), (I.sup.4'), (I.sup.5'), (I.sup.2a'),
(I.sup.3a'), (I.sup.4a'), (I.sup.5a'), (I.sup.2b'), (I.sup.3b'),
(I.sup.4b'), (I.sup.5b'), (I.sup.2c'), (I.sup.3c'), (I.sup.4c'),
(I.sup.5c') or (I.sup.6').
[0336] The compounds of the invention represented by the above
described Formula (I) may include enantiomers depending on the
presence of chiral centres or isomers depending on the presence of
multiple bonds (e.g. Z, E). The single isomers, enantiomers or
diastereoisomers and mixtures thereof fall within the scope of the
present invention.
[0337] For the sake of clarity the expression "a compound according
to Formula (I), wherein R.sub.1, R.sub.2, R.sub.3, R.sub.3',
R.sub.5, R.sub.5', R.sub.6, R.sub.6', X, Y, m, n, q and r are as
defined in the description in the detailed description" would (just
like the expression "a compound of Formula (I) as defined in any
one of claims 1 to 11" found in the claims) refer to "a compound
according to Formula (I)", wherein the definitions of the
respective substituents R.sub.1 etc. (also from the cited claims)
are applied. In addition, this would also mean, though (especially
in regards to the claims) that also one or more disclaimers defined
in the description (or used in any of the cited claims like e.g.
claim 1) would be applicable to define the respective compound.
Thus, a disclaimer found in e.g. claim 1 would be also used to
define the compound "of Formula (I) as defined in any one of claims
1 to 11".
[0338] In general the processes are described below in the
experimental part. The starting materials are commercially
available or can be prepared by conventional methods.
[0339] A preferred aspect of the invention is also a process for
the production of a compound according to Formula (I).
[0340] A preferred aspect of the invention is a process for the
production of a compound according to Formula (I),
##STR00222##
and wherein R.sub.1, R.sub.2, R.sub.3, R.sub.3', R.sub.5, R.sub.5',
R.sub.6, R.sub.6', m, n, q, r, X and Y are as defined in the
description, following schemes 1 to 4.
[0341] In all processes and uses described underneath, the values
of R.sub.1, R.sub.1', R.sub.2, R.sub.3, R.sub.3', R.sub.4,
R.sub.4', R.sub.5, R.sub.5', R.sub.6, R.sub.6', m, n, p, q, r, X
and Y are as defined in the description (unless otherwise stated),
LG represents a leaving group such as halogen, mesylate, tosylate
or triflate, with the proviso that when Y.dbd.CO it can only be
chloro or bromo. V represents an aldehyde or another leaving group
(such as halogen, mesylate, tosylate or triflate), P represents a
suitable protecting group (preferably Boc) and P' represents an
orthogonal protecting group (preferably 4-methoxybenzyl, benzyl or
benzhydryl).
[0342] A preferred embodiment of the invention is a process for the
preparation of compounds of general formula (I) wherein R.sub.1 is
--(CR.sub.4R.sub.4').sub.pR.sub.1' (compounds of formula Ia), said
process comprises:
a) an intramolecular cyclization of a compound of formula VIIa
##STR00223## [0343] or b) the reaction of a compound of formula
VIIIH
[0343] ##STR00224## [0344] with a compound of formula IX, X or
XI,
[0344] ##STR00225## [0345] or c1) when V is CH.sub.2, by the
alkylation of a compound of formula XIV
[0345] ##STR00226## [0346] with a compound of formula XV
[0346] ##STR00227## [0347] being the compound of formula XV an
alkylating agent and V a leaving group, or alternatively by the
reductive amination reaction of a compound of formula XIV with a
compound of formula XV, being the compound of formula XV an
aldehyde and V a C(O)H group; or c2) when Y is C(O), by the
alkylation of a compound of formula XIV
[0347] ##STR00228## [0348] with a compound of formula XV
[0348] ##STR00229## [0349] being the compound of formula XV an
alkylating agent and V a leaving group.
[0350] In another embodiment of the invention is a process for the
preparation of compounds of general formula (I) wherein R.sub.1 is
--(CR.sub.4R.sub.4').sub.pR.sub.1' (compounds of formula Ia), said
process comprises an intramolecular cyclization of a compound of
formula VIIa
##STR00230##
[0351] In another embodiment of the invention is a process for the
preparation of compounds of general formula (I) wherein R.sub.1 is
--(CR.sub.4R.sub.4').sub.pR.sub.1' (compounds of formula Ia), said
process comprises the reaction of a compound of formula VIIIH
##STR00231## [0352] with a compound of formula IX, X or XI,
##STR00232##
[0353] In another embodiment of the invention is a process for the
preparation of compounds of general formula (I) wherein R.sub.1 is
--(CR.sub.4R.sub.4').sub.pR.sub.1' and Y is CH.sub.2, (compounds of
formula Ia), said process comprises the alkylation of a compound of
formula XIV
##STR00233## [0354] with a compound of formula XV
[0354] ##STR00234## [0355] being the compound of formula XV an
alkylating agent and V a leaving group, or alternatively by the
reductive amination reaction of a compound of formula XIV with a
compound of formula XV, being the compound of formula XV an
aldehyde and V a C(O)H group;
[0356] In another embodiment of the invention is a process for the
preparation of compounds of general formula (I) wherein R.sub.1 is
--(CR.sub.4R.sub.4').sub.pR.sub.1' and Y is C(O), by the alkylation
of a compound of formula XIV
##STR00235## [0357] with a compound of formula XV
[0357] ##STR00236## [0358] being the compound of formula XV an
alkylating agent and V a leaving group.
[0359] In another preferred embodiment of the invention is a
process for the preparation, of compounds of general formula (I)
wherein R.sub.1 is --(CR.sub.4R.sub.4').sub.pR.sub.1', Y represents
CO and R.sub.3 and R.sub.3' taken together with the connecting
C-atom form a cyclopropyl (compounds of formula Id),
##STR00237##
said process comprises [0360] a) the treatment with a strong base
of a compound of formula Ic wherein R.sub.s.dbd.R.sub.s'.dbd.H and
s=1
##STR00238##
[0360] or [0361] b) a cyclopropanation reaction on a compound of
formula XXI
[0361] ##STR00239## [0362] Or [0363] c) the alkylation of a
compound of formula XXV
[0363] ##STR00240## [0364] with a compound of formula XV
[0364] ##STR00241## [0365] being the compound of formula XV an
alkylating agent and V a leaving group; [0366] or [0367] d) the
reaction of a compound of formula XIXH
[0367] ##STR00242## [0368] with a compound of formula IX, X or
XI,
##STR00243##
[0369] In another preferred embodiment of the invention is a
process for the preparation, of compounds of general formula (I)
wherein R.sub.1 is --(CR.sub.4R.sub.4').sub.pR.sub.1', Y represents
CO and R.sub.3 and R.sub.3' taken together with the connecting
C-atom form a cyclopropyl (compounds of formula Id),
##STR00244##
said process comprises [0370] a) the treatment with a strong base
of a compound of formula Ic wherein R.sub.s.dbd.R.sub.s'.dbd.H and
s=1
##STR00245##
[0371] In another preferred embodiment of the invention is a
process for the preparation, of compounds of general formula (I)
wherein R.sub.1 is --(CR.sub.4R.sub.4').sub.pR.sub.1', Y represents
CO and R.sub.3 and R.sub.3' taken together with the connecting
C-atom form a cyclopropyl (compounds of formula Id),
##STR00246##
said process comprises a cyclopropanation reaction on a compound of
formula XXI
##STR00247##
[0372] In another preferred embodiment of the invention is a
process for the preparation, of compounds of general formula (I)
wherein R.sub.1 is --(CR.sub.4R.sub.4').sub.pR.sub.1', Y represents
CO and R.sub.3 and R.sub.3' taken together with the connecting
C-atom form a cyclopropyl (compounds of formula Id),
##STR00248## [0373] said process comprises the alkylation of a
compound of formula XXV
[0373] ##STR00249## [0374] with a compound of formula XV
[0374] ##STR00250## [0375] being the compound of formula XV an
alkylating agent and V a leaving group.
[0376] In another preferred embodiment of the invention is a
process for the preparation, of compounds of general formula (I)
wherein R.sub.1 is --(CR.sub.4R.sub.4').sub.pR.sub.1', Y represents
CO and R.sub.a and R.sub.3' taken together with the connecting
C-atom form a cyclopropyl (compounds of formula Id),
##STR00251## [0377] a) said process comprises the reaction of a
compound of formula XIXH
[0377] ##STR00252## [0378] with a compound of formula IX, X or
XI,
##STR00253##
[0379] In another particular embodiment a compound of Formula II,
IIP, III, IIIP, IVa, IVb, Vb, VbP, XII, XIIP, Va, VaP, VI, VIIb,
VIIbP, XIII, XIIIP, VIIla, VIIaP, XVI, XVIP, XVIH, XIV, XIVP, XIVH,
Ia, VIIIP, VIIIH, XV, IX, X, XI, Ie, XXP, XXH, XXI, XXIP, XXIH, Ib,
XVIIP, XVIIH, Ic, XVIIIP, Id, XIXP, XIXH, XXIII, XXIIIP, XXIIIH,
XXV, XXVP, XXVH, XXII, XXIIP, XXIIH, XXIV, XXIVP, XXIVH, If, XXVIP,
XXVIH, XXVIIa, Ig, XXVIIIP, XXVIIH, XXVIIb, Ih, XXIXP, XXIXH,
XXVIIc, Ib, XVIIP, XVIIH, XXXII, XXXIIP, XXXIIH, XXXIV, XXXIVP,
XXXIVH, XXXI, XXXIP, XXXIH, XXXIII, XXXIIIP, XXXIIIH, XXXV, Ij,
XXXVIP, XXXVIH, Ih, XXIXP, XXIXH, Ii, XXXP or XXXH,
##STR00254## ##STR00255## ##STR00256## ##STR00257## ##STR00258##
##STR00259## ##STR00260##
is used for the preparation of a compound of Formula (I).
[0380] The obtained reaction products may, if desired, be purified
by conventional methods, such as crystallisation and
chromatography. Where the above described processes for the
preparation of compounds of the invention give rise to mixtures of
stereoisomers, these isomers may be separated by conventional
techniques such as preparative chromatography. If there are chiral
centers the compounds may be prepared in racemic form, or
individual enantiomers may be prepared either by enantiospecific
synthesis or by resolution.
[0381] One preferred pharmaceutically acceptable form of a compound
of the invention is the crystalline form, including such form in
pharmaceutical composition. In the case of salts and also solvates
of the compounds of the invention the additional ionic and solvent
moieties must also be non-toxic. The compounds of the invention may
present different polymorphic forms, it is intended that the
invention encompasses all such forms.
[0382] Another aspect of the invention refers to a pharmaceutical
composition which comprises a compound according to the invention
as described above according to general formula I or a
pharmaceutically acceptable salt or steroisomer thereof, and a
pharmaceutically acceptable carrier, adjuvant or vehicle. The
present invention thus provides pharmaceutical compositions
comprising a compound of this invention, or a pharmaceutically
acceptable salt or stereoisomers thereof together with a
pharmaceutically acceptable carrier, adjuvant, or vehicle, for
administration to a patient.
[0383] Examples of pharmaceutical compositions include any solid
(tablets, pills, capsules, granules etc.) or liquid (solutions,
suspensions or emulsions) composition for oral, topical or
parenteral administration.
[0384] In a preferred embodiment the pharmaceutical compositions
are in oral form, either solid or liquid. Suitable dose forms for
oral administration may be tablets, capsules, syrops or solutions
and may contain conventional excipients known in the art such as
binding agents, for example syrup, acacia, gelatin, sorbitol,
tragacanth, or polyvinylpyrrolidone; fillers, for example lactose,
sugar, maize starch, calcium phosphate, sorbitol or glycine;
tabletting lubricants, for example magnesium stearate;
disintegrants, for example starch, polyvinylpyrrolidone, sodium
starch glycollate or microcrystalline cellulose; or
pharmaceutically acceptable wetting agents such as sodium lauryl
sulfate.
[0385] The solid oral compositions may be prepared by conventional
methods of blending, filling or tabletting. Repeated blending
operations may be used to distribute the active agent throughout
those compositions employing large quantities of fillers. Such
operations are conventional in the art. The tablets may for example
be prepared by wet or dry granulation and optionally coated
according to methods well known in normal pharmaceutical practice,
in particular with an enteric coating.
[0386] The pharmaceutical compositions may also be adapted for
parenteral administration, such as sterile solutions, suspensions
or lyophilized products in the appropriate unit dosage form.
Adequate excipients can be used, such as bulking agents, buffering
agents or surfactants.
[0387] The mentioned formulations will be prepared using standard
methods such as those described or referred to in the Spanish and
US Pharmacopoeias and similar reference texts.
[0388] Administration of the compounds or compositions of the
present invention may be by any suitable method, such as
intravenous infusion, oral preparations, and intraperitoneal and
intravenous administration. Oral administration is preferred
because of the convenience for the patient and the chronic
character of the diseases to be treated.
[0389] Generally an effective administered amount of a compound of
the invention will depend on the relative efficacy of the compound
chosen, the severity of the disorder being treated and the weight
of the sufferer. However, active compounds will typically be
administered once or more times a day for example 1, 2, 3 or 4
times daily, with typical total daily doses in the range of from
0.1 to 1000 mg/kg/day.
[0390] The compounds and compositions of this invention may be used
with other drugs to provide a combination therapy. The other drugs
may form part of the same composition, or be provided as a separate
composition for administration at the same time or at different
time.
[0391] Another aspect of the invention refers to the use of a
compound of the invention or a pharmaceutically acceptable salt or
isomer thereof in the manufacture of a medicament.
[0392] Another aspect of the invention refers to a compound of the
invention according as described above according to general formula
I, or a pharmaceutically acceptable salt or isomer thereof, for use
as a medicament for the treatment of pain. Preferably the pain is
medium to severe pain, visceral pain, chronic pain, cancer pain,
migraine, inflammatory pain, acute pain or neuropathic pain,
allodynia or hyperalgesia. This may include mechanical allodynia or
thermal hyperalgesia.
[0393] Another aspect of the invention refers to the use of a
compound of the invention in the manufacture of a medicament for
the treatment or prophylaxis of pain.
[0394] In a preferred embodiment the pain is selected from medium
to severe pain, visceral pain, chronic pain, cancer pain, migraine,
inflammatory pain, acute pain or neuropathic pain, allodynia or
hyperalgesia, also preferably including mechanical allodynia or
thermal hyperalgesia.
[0395] Another aspect of this invention relates to a method of
treating or preventing pain which method comprises administering to
a patient in need of such a treatment a therapeutically effective
amount of a compound as above defined or a pharmaceutical
composition thereof. Among the pain syndromes that can be treated
are medium to severe pain, visceral pain, chronic pain, cancer
pain, migraine, inflammatory pain, acute pain or neuropathic pain,
allodynia or hyperalgesia, whereas this could also include
mechanical allodynia or thermal hyperalgesia.
[0396] The present invention is illustrated below with the aid of
examples. These illustrations are given solely by way of example
and do not limit the general spirit of the present invention.
General Experimental Part (Methods and Equipment of the Synthesis
and Analysis
Scheme 1:
[0397] A 4-step process is described for the preparation of
compounds of general formula (I) wherein R.sub.1 is
--(CR.sub.4R.sub.4').sub.pR.sub.1' (compounds of formula Ia)
starting from a ketone of formula II, as shown in the following
scheme:
##STR00261## ##STR00262##
wherein R.sub.1', R.sub.2, R.sub.3, R.sub.3', R.sub.4, R.sub.4',
R.sub.5, R.sub.5', R.sub.6, R.sub.6', X, Y, m, n, p, q and r have
the meanings as defined above for a compound of formula (I), LG
represents a leaving group such such as halogen, mesylate, tosylate
or triflate, with the proviso that when Y.dbd.CO it can only be
chloro or bromo, V represents an aldehyde or another leaving group
(such as halogen, mesylate, tosylate or triflate). P represents a
suitable protecting group (preferably Boc) and P' represents an
orthogonal protecting group (preferably 4-methoxybenzyl, benzyl or
benzhydryl).
[0398] The 4 step-process is carried out as described below:
Step1: A compound of formula III is prepared by treating a compound
of formula II with a suitable methyl-transfer reagent such as
trimethylsulfoxonium iodide or trimethylsulfonium iodide, in a
suitable aprotic solvent such as dimethylsulfoxide or
1,2-dimethoxyethane or mixtures, and in the presence of a strong
base such as sodium hydride or potassium tert-butoxide, at a
suitable temperature, preferably comprised between 0.degree. C. and
60.degree. C. Step2: A compound of formula Va is prepared by
reacting a compound of formula III with an amine of formula IVa, in
a suitable solvent such as an alcohol, preferably ethanol-water
mixtures, at a suitable temperature comprised between room
temperature and the reflux temperature. Step3: A compound of
formula Vila is prepared by reacting a compound of formula Va with
a compound of formula VI. Depending on the meaning of Y, the
compound of formula VI can be of different nature and different
reaction conditions will apply: [0399] a) When Y represents CO, VI
is an acylating agent. The acylation reaction is carried out in a
suitable solvent, such as dichioromethane or ethyl acetate-water
mixtures; in the presence of an organic base such as triethylamine
or diisopropylethylamine or an inorganic base such as
K.sub.2CO.sub.3; and at a suitable temperature, preferably
comprised between -78.degree. C. and room temperature. [0400] b)
When Y represents CH.sub.2, VI is an alkylating agent. The
alkylation reaction may be carried out in a suitable solvent, such
as acetonitrile, dichloromethane, tetrahydrofuran, 1,4-dioxane or
dimethylformamide; in the presence of an inorganic base such as
K.sub.2CO.sub.3, Cs.sub.2CO.sub.3 or NaH, or an organic base such
as triethylamine or diisopropylethylamine, at a suitable
temperature comprised between room temperature and the reflux
temperature. The OH group present may need protection previous to
the alkylation reaction. Step4: The intramolecular cyclization of a
compound of formula Vila renders a compound of formula Ia. The
cyclization reaction is carried out in a suitable solvent, such as
tetrahydrofuran; in the presence of a strong base such as potassium
tert-butoxide or sodium hydride; and at a suitable temperature,
comprised between -78.degree. C. and the reflux temperature,
preferably cooling.
[0401] Alternatively, the group
--(CR.sub.5R.sub.5').sub.mX(CR.sub.6R.sub.6').sub.nR.sub.2 can be
incorporated in the last step of the synthesis by reaction of a
compound of formula VIIIH with a compound of formula IX, X or XI,
as shown in Scheme 1. A compound of formula VIIIH is obtained by
deprotection of a compound of formula VIIIP, wherein P represents a
suitable protecting group, preferably Boc (tert-butoxycarbonyl).
When the protecting group is Boc, the deprotection can be conducted
by adding a solution of a strong acid such as HCl, in a suitable
solvent such as diethyl ether, 1,4-dioxane or methanol, or with
trifluoroacetic acid in dichloromethane. A compound of formula
VIIIP is prepared from a compound of formula IIP following the same
sequence described for the synthesis of compounds of formula
Ia.
[0402] The alkylation reaction between a compound of formula VIIIH
(or a suitable salt such as trifluoroacetate or hydrochloride) and
a compound of formula IX is carried out in a suitable solvent, such
as acetonitrile, dichloromethane, 1,4-dioxane or dimethylformamide,
preferably in acetonitrile; in the presence of an inorganic base
such as K.sub.2CO.sub.3 or Cs.sub.2CO.sub.2, or an organic base
such as triethylamine or diisopropylethylamine, preferably
K.sub.2CO.sub.3: at a suitable temperature comprised between room
temperature and the reflux temperature, preferably heating, or
alternatively, the reactions can be carried out in a microwave
reactor. Additionally, an activating agent such as Nal can be
used.
[0403] The reductive amination reaction between a compound of
formula VIIIH and a compound of formula X is carried out in the
presence of a reductive reagent, preferably sodium
triacetoxyborohydride, in an aprotic solvent, preferably
tetrahydrofuran or dichloroethane, optionally in the presence of an
acid, preferably acetic acid.
[0404] The condensation reaction between a compound of general
formula VIIIH and a compound of formula XI is preferably carried
out in a suitable solvent, such as ethanol, isopropanol, n-butanol
or 2-methoxyethanol, optionally in the presence of an organic base
such as triethylamine or diisopropylethylamine, at a suitable
temperature comprised between room temperature and the reflux
temperature, preferably heating, or alternatively, the reactions
can be carried out in a microwave reactor.
[0405] In another alternative approach, the
--(CR.sub.4R.sub.4').sub.pR.sub.1' substituent can be incorporated
later in the sequence by the reaction of a compound of formula XIV
with a compound of formula XV. Depending on the meaning of Y, V can
be of different nature and different reaction conditions will
apply: [0406] a) When Y is CH.sub.2, compound XV is an alkylating
agent and V represents a leaving group such as halogen, mesylate,
tosylate or triflate. The alkylation reaction is carried out under
the same reaction conditions described above for the reaction of a
compound of formula VIIIH and a compound of formula IX.
Alternatively, compound XV can be an aldehyde wherein V represents
a C(O)--H group. The reductive amination reaction is carried out
under the same reaction conditions described above for the reaction
of a compound of formula VIIIH and a compound of formula X. [0407]
b) When Y is C(O), compound XV is an alkylating agent and V
represents a leaving group such as halogen, mesylate, tosylate or
triflate. This alkylation reaction is carried out in an aprotic
solvent, preferably dimethylformamide, in the presence of an
inorganic base such as NaH, at a suitable temperature, preferably
between room temperature and 60.degree. C.
[0408] A compound of formula XIV is synthesized following an
analogous sequence as described for the synthesis of compounds of
formula Ia, but effecting step 2 using ammonia instead of an amine
IVa. Alternatively, when Y is C(O), a compound of formula XIV can
be prepared by reaction of a compound of formula XIVH (prepared
from a compound of formula XIVP, wherein P represents a suitable
protecting group) with a compound of formula IX, X or XI, as
described above.
[0409] Additionally, a compound of formula XIV can be prepared from
a compound of formula XVI, wherein P' represents an orthogonal
protecting group. When Y is C(O), P' is preferably a
4-methoxybenzyl group and the deprotection reaction is carried out
with cerium ammonium nitrate in a suitable solvent such as mixtures
of acetonitrile-water or by heating in trifluoroacetic acid or
hydrochloric acid. When Y is --CH.sub.2--, P' is preferably a
4-methoxybenzyl, a benzyl or a benzhydryl group, and the
deprotection reaction is preferably carried out by hydrogenation
under hydrogen atmosphere and metal catalysis, preferably by the
use of palladium over charcoal as catalyst in a suitable solvent
such as methanol or ethanol, optionally in the presence of an acid
such as acetic acid or hydrochloric acid.
[0410] A compound of formula XVI is synthesized from a compound of
formula III following an analogous sequence as described for the
synthesis of compounds of formula Ia. Alternatively, a compound of
formula XVI can be prepared by reaction of a compound of formula
XVIH (prepared from a compound of formula XVIP, wherein P
represents a suitable protecting group) with a compound of formula
IX, X or XI, as described above.
[0411] The compounds of general formula II, IIP, IVa, IVb, VI, IX,
X, XI and XV wherein R.sub.1', R.sub.2, R.sub.3, R.sub.3', R.sub.4,
R.sub.4', R.sub.5, R.sub.5', R.sub.6, R.sub.6', X, Y, m, n, p, q
and r have the meanings as defined above, are commercially
available or can be prepared by conventional methods described in
the bibliography.
Scheme 2:
[0412] The preparation of compounds of general formula (I) wherein
Y represents CO and R.sub.3 and R.sub.3' are taken together with
the connecting C-atom to form a cycloalkyl (compounds of formula
Ib) is described in the following scheme:
##STR00263## ##STR00264##
wherein R.sub.1', R.sub.2, R.sub.4, R.sub.4', R.sub.5, R.sub.5',
R.sub.6, R.sub.6', X, Y, m, n, p, q and r have the meanings as
defined above for a compound of formula (I), s represents 1, 2, 3
or 4, R.sub.s and R.sub.s' represent hydrogen or alkyl, LG
represents a leaving group such as halogen, mesylate, tosylate or
triflate, V represents another leaving group (such as halogen,
mesylate, tosylate or triflate), P represents a suitable protecting
group (preferably Boc), P' represents an orthogonal protecting
group (preferably 4-methoxybenzyl), and Q represents methyl or
benzyl.
[0413] A compound of formula Ib can be prepared from a compound of
formula Ic by treatment with a strong base such as lithium
diisopropylamide or potassium tert-butoxide, in an aprotic solvent
such as tetrahydrofuran, at a suitable temperature, preferably
cooling. And analogously, a compound of formula Id (wherein
R.sub.s.dbd.R.sub.s'.dbd.H and s=1) can be prepared from a compound
of formula Ic under the same reaction conditions.
[0414] Alternatively, compounds of formula Id can be prepared from
compounds of formula XXI. The cyclopropanation reaction is carried
out using a suitable methyl-transfer reagent such as
trimethylsulfoxonium iodide or trimethylsulfonium iodide, in a
suitable aprotic solvent such as dimethylsulfoxide, and in the
presence of a strong base such as sodium hydride or potassium
tert-butoxide, at a suitable temperature, preferably comprised
between room temperature and 60.degree. C. Alternatively, typical
Simmons-Smith reaction conditions could be used, comprising the
treatment of a compound of formula XXI with diiodomethane, a zinc
source such as zinc-copper, zinc iodide or diethylzinc, in a
suitable aprotic solvent, such as diethyl ether.
[0415] Compounds of formula XXI can be prepared from a compound of
formula Ie wherein Q represents methyl or benzyl. The elimination
reaction is carried out in the presence of a base, such as
potassium tert-butoxide, in a suitable solvent, such as
tetrahydrofuran.
[0416] In another alternative approach, the
--(CR.sub.4R.sub.4').sub.pR.sub.1' substituent can be incorporated
later in the synthesis. Thus, compounds of formula Ib and Id can be
prepared from compounds of formula XXIII and XXV, respectively,
following the reaction conditions described in Scheme 1 for the
preparation of compounds of formula Ia from compounds of formula
XIV. The compounds of formula XXIII and XXV can be prepared from
suitable protected precursors XXII and XXIV, respectively,
following the conditions described in Scheme 1.
[0417] In addition, the group
--(CR.sub.5R.sub.5').sub.mX(CR.sub.6R.sub.6').sub.nR.sub.2 can be
incorporated in the last step of the synthesis to prepare compounds
of formula Ib and Id from suitable protected precursors, by
deprotection followed by reaction with a compound of formula IX or
X or XI, as described in Scheme 1 for the preparation of compounds
of formula Ia.
[0418] The compounds of general formula Ic and Ie can be prepared
by the procedures described in Scheme 1 from a compound of formula
Va using suitable starting materials. The compounds of general
formula XXII and XXIV can be prepared following the procedures
described in Scheme 2 for the preparation of compounds of formula
Ib and Id using the corresponding protected starting materials.
Scheme 3 and Scheme 4
[0419] Compounds of formula (I) can also be prepared starting from
other compounds of formula (I), as described in Schemes 3 and 4
below.
[0420] Compounds of formula Ib, Ig and Ih can be prepared from a
compound of formula If as shown in Scheme 3:
##STR00265##
wherein R.sub.1', R.sub.2, R.sub.3, R.sub.3', R.sub.4, R.sub.4',
R.sub.5, R.sub.5', R.sub.6, R.sub.6', X, m, n, p, q and r have the
meanings as defined above for a compound of formula (I), s
represents 1, 2, 3 or 4, R.sub.s and R.sub.s' represent hydrogen or
alkyl, LG, X' and X'' independently represent a leaving group such
as halogen, mesylate, tosylate or triflate, and P represents a
suitable protecting group (preferably Boc).
[0421] A compound of formula Ig can be prepared by treating a
compound of formula If with an alkylating agent of formula XXVIIa
in the presence of a strong base such as lithium diisopropylamide
or potassium tert-butoxide, in an aprotic solvent such as
tetrahydrofuran, at a suitable temperature, preferably comprised
between -78.degree. C. and room temperature. A second alkylation
can be performed under the same reaction conditions to prepare a
compound of formula Ih. An analogous double-alkylation process can
be used for the preparation of compounds of formula Ib, by reacting
a compound of formula If with an alkylating agent of formula
XXVIIc, as an alternative to the procedure described in Scheme 2
for the preparation of compounds of formula Ib.
[0422] In addition, the group
--(CR.sub.5R.sub.5').sub.mX(CR.sub.6R.sub.6').sub.nR.sub.2 can be
incorporated in the last step of the synthesis to prepare compounds
of formula Ib, If, Ig and Ih from suitable protected precursors, by
deprotection followed by reaction with a compound of formula IX or
X or XI, under the reaction conditions described in Scheme 1 for
the preparation of compounds of formula Ia.
[0423] The compounds of general formula If and Ig can be prepared
by the procedures described in Scheme 1 using suitable starting
materials.
[0424] The compounds of general formula XXVIIa, XXVIIb and XXVIIc
wherein R.sub.3, R.sub.3', R.sub.s, R.sub.s', X', X'' and s have
the meanings as defined above, are commercially available or can be
prepared by conventional methods described in the bibliography.
[0425] Scheme 4 shows the preparation of compounds of formula (I)
wherein Y is CH.sub.2 from compounds of formula (I) wherein Y is
C(O):
##STR00266##
wherein R.sub.1', R.sub.2, R.sub.3, R.sub.3', R.sub.4, R.sub.4',
R.sub.5, R.sub.5', R.sub.6, R.sub.6', X, m, n, p, q and r have the
meanings as defined above for a compound of formula (I), LG
represents a leaving group such as halogen, mesylate, tosylate or
triflate, V represents an aldehyde or another leaving group (such
as halogen, mesylate, tosylate or triflate), P represents a
suitable protecting group (preferably Boc). P represents an
orthogonal protecting group (preferably 4-methoxybenzyl, benzyl or
benzhydryl) and Z represents OH or halogen (preferably bromo or
chloro).
[0426] The reduction reaction of a compound of formula Ih or Ij to
yield a compound of formula Ii can be performed using a suitable
reducing agent such as lithium aluminium hydride,
borane-tetrahydrofuran complex or borane-dimethyl sulphide complex,
in a suitable solvent such as tetrahydrofuran or diethyl ether, at
a suitable temperature comprised between room temperature and the
reflux temperature, preferably heating.
[0427] The reduction reaction can also be performed on a suitable
precursor (compounds of formula XXXI or XXXII) or a protected
derivative (compounds of formula XXIXP, XXXIP, XXXIIP or XXXVIP,
wherein A=P). When P represents Boc, borane is the preferred
reducing agent.
[0428] The compounds of general formula Ih can be prepared by the
procedures described in Schemes 1 to 3 using suitable starting
materials, or they can be prepared from a compound of formula XXXI
or XXXII. The deprotection of a compound of formula XXXII to give a
compound of formula XXXI and the subsequent reaction with a
compound of formula XV to yield a compound of formula Ih are
performed following the procedures described in Scheme 1.
[0429] The compounds of general formula XXXI and XXXII can be
prepared according to the procedures described in Scheme 1 using
suitable starting materials.
[0430] Accordingly, the compounds of general formula Ii may be
prepared from a compound of formula XXXIII or XXXIV following an
analogous procedure.
[0431] A compound of formula Ij is prepared by reacting a compound
of formula XXXIII with an acylating agent of formula XXXV. When Z
is halogen, the reaction is carried out in a suitable solvent, such
as dichloromethane, tetrahydrofuran, ethyl acetate or ethyl
acetate-water mixtures; in the presence of an organic base such as
triethylamine or diisopropylethylamine or an inorganic base such as
K.sub.2CO.sub.3; and at a suitable temperature, preferably
comprised between 0.degree. C. and room temperature. Additionally,
an activating agent such as 4-dimethylaminopyridine can be
used.
[0432] When Z is OH, the acylation reaction is carried out using a
suitable coupling reagent such as
N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide (EDC),
dicyclohexylcarbodiimide (DCC),
N-[(dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N-meth-
ylmethanaminium hexafluorophosphate N-oxide (HATU) or
N,N,N'N'-tetramethyl-O-(1H-benzotriazol-1-yl)uronium
hexafluorophosphate (HBTU), optionally in the presence of
1-hydroxybenzotriazole, optionally in the presence of an organic
base such as N-methylmorpholine or diisopropylethylamine, in a
suitable solvent such as dichloromethane or dimethylformamide, and
at a suitable temperature, preferably at room temperature.
[0433] In addition, the group
--(CR.sub.5R.sub.5').sub.mX(CR.sub.6R.sub.6').sub.nR.sub.2 may be
incorporated at different stages of the synthesis to prepare
compounds of formula Ih, Ii and Ij from suitable protected
precursors, by deprotection followed by reaction with a compound of
formula IX or X or XI, as described in Scheme 1 for the preparation
of compounds of formula Ia.
[0434] Moreover, certain compounds of the present invention can
also be obtained starting from other compounds of formula (I) by
appropriate conversion reactions of functional groups, in one or
several steps, using well-known reactions in organic chemistry
under standard experimental conditions.
[0435] In addition, a compound of formula I that shows chirality
can also be obtained by resolution of a racemic compound of formula
I either by chiral preparative HPLC or by crystallization of a
diastereomeric salt or co-crystal. Alternatively, the resolution
step can be carried out at a previous stage, using any suitable
intermediate.
EXAMPLES
[0436] The following abbreviations are used in the examples:
ACN: acetonitrile AcOH: acetic acid Boc: tert-butoxycarbonyl Conc:
concentrated DCM: dichloromethane DEA: diethylamine EtOH: ethanol
EX: example h: hour/s HPLC: high performance liquid chromatography
INT: intermediate LDA: lithium diisopropylamide MeOH: methanol MS:
mass spectrometry Min.: minutes Quant: quantitative Ret.: retention
r.t.: room temperature Sat: saturated s.m.: starting material THF:
tetrahydrofuran Wt: weight
[0437] The following methods were used to determine the HPLC-MS
spectra:
Method A
Column: Gemini-NX 30.times.4.6 mm, 3 um
Temperature: 40.degree. C.
[0438] Flow: 2.0 mL/min Gradient: NH.sub.4HCO.sub.3 pH 8: ACN
(95:5)---0.5 min---(95:5)---5 min---(0:100)---1 min---(0:100)
Sample dissolved aprox. 1 mg/mL in NH.sub.4HCO.sub.3 pH 8/ACNMethod
B
Column: Kinetex EVO 50.times.4.6 mm 2.6 um
Temperature: 40.degree. C.
[0439] Flow: 2.0 mL/min Gradient: NH.sub.4HCO.sub.3 pH 8: ACN
(95:5)---0.5 min---(95:5)---6.5 min---(0:100)---1 min---(0:100)
Sample dissolved aprox. 1 mg/mL in NH.sub.4HCO.sub.3 pH 8/ACN
Method C
Column: Kinetex EVO 50.times.4.6 mm 2.6 um
Temperature: 40.degree. C.
[0440] Flow: 1.5 mL/min Gradient: NH.sub.4HCO.sub.3 pH 8: ACN
(95:5)---0.5 min---(95:5)---6.5 min---(0:100)---2 min---(0:100)
Sample dissolved aprox. 1 mg/mL in NH.sub.4HCO.sub.3 pH 8/ACN
Synthesis of Intermediate
Intermediate 1A: tert-Butyl
1-oxa-5-azaspiro[2.5]octane-5-carboxylate
##STR00267##
[0442] To a solution of potassium tert-butoxide (2.20 g, 19.6 mmol)
in DMSO (17 mL), trimethylsulfoxonium iodide (4.80 g, 21.8 mmol)
was added in portions. The mixture was stirred at r.t. for 1.5 h.
DME (4.5 mL) was added and it was cooled to 0-5.degree. C. A
solution of tert-butyl 3-oxopiperidine-1-carboxylate (3.0 g, 15.1
mmol) in a mixture of DME (4.5 mL) and DMSO (1.5 mL) was added
dropwise. The reaction mixture was stirred at 0-5.degree. C. for 1
h. It was diluted with water and ethyl acetate. The phases were
separated and the aqueous phase was back extracted with additional
ethyl acetate. The organic phases were combined, washed with water,
dried over MgSO.sub.4 and concentrated under vacuum to give the
title compound (2.36 g, 74% yield).
[0443] This method was used for the preparation of intermediates
1B-1C using suitable starting materials:
TABLE-US-00005 INT Structure Chemical name 1B ##STR00268##
tert-butyl 1-oxa-6- azaspiro[2.6]nonane-6- carboxylate 1C
##STR00269## 5-benzhydryl-oxa-5- azaspiro[2.3]hexane
Intermediate 2A: tert-Butyl
3-((ethylamino)methyl)-3-hydroxypiperidine-1-carboxylate
##STR00270##
[0445] To a solution of intermediate 1A (2.36 g, 11.1 mmol) in a
mixture of ethanol-water 9:1 (43 mL), ethylamine (17.7 mL, 70%
solution in water, 222 mmol) was added. The reaction mixture was
stirred at r.t. overnight. The solvent was removed under vacuum to
give the title compound (2.84 g, 99% yield).
[0446] This method was used for the preparation of intermediates
2B-2C using suitable starting materials:
TABLE-US-00006 INT Structure Chemical name s.m. 2B ##STR00271##
tert-butyl 4- ((ethylamino)methyl)- 4-hydroxyazepane-1- carboxylate
1B 2C ##STR00272## 1-benzhydryl-3- ((ethylamino)methyl)
azetidin-3-ol 1C
Intermediate 2D: tert-Butyl
4-hydroxy-4-((phenylamino)methyl)azepane-1-carboxylate
##STR00273##
[0448] To a solution of intermediate 1B (1.7 g, 7.5 mmol) in a
mixture of ethanol-water 9:1 (34 mL), aniline (1.37 mL, 15 mmol)
was added. The reaction mixture was heated to 100.degree. C.
overnight in an autoclave reactor. The solvent was removed under
vacuum and the residue was purified by flash chromatography, silica
gel, gradient dichloromethane to methanol:dichloromethane (1:4) to
give the title compound (2.0 g, 83% yield)
[0449] This method was used for the preparation of intermediates
2E-2H using suitable starting materials:
TABLE-US-00007 INT Structure Chemical name s.m. 2E ##STR00274##
tert-butyl 3-hydroxy-3- ((phenylamino)methyl)- piperidine-1-
carboxylate 1A 2F ##STR00275## tert-butyl 3-
((benzylamino)methyl)-3- hydroxypiperidine-1- carboxylase 1A 2G
##STR00276## tert-butyl 4- ((benzylamino)methyl)- 4-hydroxyazepane-
1-carboxylate 1B 2H ##STR00277## 1-benzhydryl-3-
((benzylamino)methyl)- azetidin-3-ol 1C
Intermediate 2I:
1-Benzhydryl-3-((isopropylamino)methyl)azetidin-3-ol
##STR00278##
[0451] The method described for the synthesis of Intermediate 2A
was used for the preparation of the title compound using
Intermediate 1C and isopropylamine as starting materials.
Intermediate 2J: tert-Butyl
4-hydroxy-4-((methylamino)methyl)azepan-1-carboxylate
##STR00279##
[0453] The method described for the synthesis of Intermediate 2A
was used for the preparation of the title compound using
Intermediate 1B and methylamine as starting materials.
Intermediate 3A: tert-Butyl
12-ethyl-13-oxo-4-oxa-7,12-diazadispiro[2.1.5.3]tridecane-7-carboxylate
##STR00280##
[0454] Step 1. tert-Butyl
3-((2-bromo-4-chloro-N-ethylbutanamido)methyl)-3-hydroxypiperidine-1-carb-
oxylate
[0455] To a solution of intermediate 2A (2.84 g, 11.0 mmol) in
ethyl acetate (30 mL), a solution of K.sub.2CO.sub.3 (2.75 g, 19.9
mmol) in water (21 mL) was added. After cooling to 0-5.degree. C.,
a solution of 2-bromo-4-chlorobutanoyl chloride (prepared as
described in U.S. Pat. No. 6,114,541A1 Ex1) (3.30 g, 15.0 mmol) in
ethyl acetate (15 mL) was added dropwise. The reaction mixture was
stirred at 0-5.degree. C. for 1 h and then it was diluted with
water. The layers were separated and the aqueous phase was
extracted with ethyl acetate. The organic phases were combined,
washed with 0.5 M HCl aqueous solution and then NaHCO.sub.3 sat
solution, dried over MgSO.sub.4, filtered and concentrated to
dryness to give the title compound (3.90 g, crude product).
Step 2. Title Compound
[0456] A solution of the crude product obtained in step 1 (3.70 g,
8.38 mmol) in THF (37 mL) was cooled under nitrogen to -78.degree.
C. After addition of potassium tert-butoxide solution (16.8 mL, 1M
in THF, 16.8 mmol), the reaction mixture was stirred at -30.degree.
C. for 2 h. It was then warmed-up to 0-5.degree. C. and additional
potassium tert-butoxide solution (16.8 mL, 1M in THF, 16.8 mmol)
was added. The mixture was stirred at 0-5.degree. C. for 2 h.
NH.sub.4Cl sat solution was then added, and the aqueous phase was
extracted with ethyl acetate. The organic phases were combined,
dried over MgSO.sub.4, filtered and concentrated under vacuum. The
residue was purified by flash chromatography, silica gel, gradient
DCM to MeOH:DCM (1:8) to give the title compound (904 mg, 25% yield
for the 2 steps).
[0457] This method was used for the preparation of inter mediates
3B-3I using suitable starting materials:
TABLE-US-00008 INT Structure Chemical name s.m. 3B ##STR00281##
tert-butyl 13-ethyl-14-oxo- 4-oxa-8,13-
diazadispiro[2.1.6.3]tetradecane- 8-carboxylate 2B 3C ##STR00282##
7-(dipbenylmethyl)-10- ethyl-4-oxa-7,10-
diazadispiro[2.1.3.3]undecan- 11-one 2C 3D ##STR00283## tert-buty1
12-phenyl-13- oxo-4-oxa-7,12- diazadispiro[2.1.5.3]tridecane-
7-carboxylate 2E 3E ##STR00284## tert-butyl 13-phenyl-14-
oxo-4-oxa-8,13- diazadispiro[2.1.6.3]tetradecane- 8-carboxylate 2D
3F ##STR00285## tert-butyl 12-benzyl-13- oxo-4-oxa-7,12-
diazadispiro[2.1.5.3]tridecane- 7-carboxylate 2F 3G ##STR00286##
tert-butyl 13-benzyl-14- oxo-4-oxa-8,13-
diazadispiro[2.1.6.3]tetradecane- 8-carboxylate 2G 3H ##STR00287##
10-benzyl-7- (diphenylmethyl)-4-oxa- 7,10-
diazadispiro[2.1.3.3]undecan- 11-one 2H 3I ##STR00288## tert-butyl
13-methyl- 14-oxo-4-oxa-8.13- diazadispiro[2.1.6.3]tetradecane-
8-carboxylate 2J
Intermediate 3J: tert-Butyl
4-ethyl-2-methyl-3-oxo-1-oxa-4,9-diazaspiro[5.6]dodecane-9-carboxylate
##STR00289##
[0458] Step 1. tert-Butyl
4-((2-Chloro-N-ethylpropanamido)methyl)-4-hydroxyazepane-1-carboxylate
[0459] To a solution of intermediate 2B (3.76 g, 13.8 mmol) in
ethyl acetate (38 mL), a solution of K.sub.2CO.sub.3 (5.34 g, 38.7
mmol) in water (26 mL) was added. After cooling to 0-5.degree. C.,
a solution of 2-chloropropanoyl chloride (1.82 mL, 18.8 mmol) in
ethyl acetate (15 mL) was added dropwise. The reaction mixture was
stirred at 0-5.degree. C. for 1 h and then it was diluted with
water. The layers were separated and the aqueous phase was
extracted with ethyl acetate. The organic phases were combined,
washed with cold 0.5 M HCl aqueous solution and then NaHCO.sub.3
sat solution, dried over MgSO.sub.4, filtered and concentrated to
dryness to give the title compound (4.5 g, crude product).
Step 2. Title Compound
[0460] A solution of the crude product obtained in step 1 (4.5 g,
12.4 mmol) in dry THF (45 mL) was cooled under nitrogen to
-78.degree. C. After addition of potassium tert-butoxide solution
(18.6 mL, 1M in THF, 18.6 mmol), the reaction mixture was stirred
at -78.degree. C. for 1 h. NH.sub.4Cl sat solution was then added,
and the aqueous phase was extracted with ethyl acetate. The organic
phases were combined, dried over MgSO.sub.4, filtered and
concentrated under vacuum to give the title compound (3.95 g, 89%
yield for the 2 steps).
[0461] This method was used for the preparation of intermediates
3K-3Q using suitable starting materials:
TABLE-US-00009 INT Structure Chemical name s.m. 3K ##STR00290##
tert-butyl 4-benzyl-2,2- dimethyl-3-oxo-1-oxa-4,9-
diazaspiro[5.6]decane- 9-carboxylate 2G 3L ##STR00291##
(2R)-tert-butyl 4-ethyl-2- methyl-3-oxo-1-oxa-4,9-
diazaspiro[5.6]dodecane- 9-carboxylate 2B 3M ##STR00292##
(2S)-tert-butyl 4-ethyl-2- methyl-3-oxo-1-oxa-4,9-
diazaspiro[5.6]dodecane- 9-carboxylate 2B 3N ##STR00293##
(R)-2-benzhydryl-8-ethyl- 6-methyl-5-oxa-2,8-
diazaspiro[3.5]nonan-7- one 2C 3O ##STR00294##
(S)-2-benzhydryl-8-ethyl- 6-methyl-5-oxa-2,8-
diazaspiro[3.5]nonan-7- one 2C 3P ##STR00295## (R)-2-benzhydryl-8-
isopropyl-6-methyl-5-oxa- 2,8-diazaspiro[3.5]nonan- 7-one 2I 3Q
##STR00296## (S)-2-benzhydryl-8- isopropyl-6-methyl-5-oxa-
2,8-diazaspiro[3.5]nonan- 7-one 2I
[0462] This method is also used for the preparation of
intermediates 3R-3S using suitable starting materials:
TABLE-US-00010 3R ##STR00297## (2R)-tert-butyl 4-benzyl-2-
methyl-3-oxo-1-oxa-4,9- diazaspiro[5.6]dodecane- 9-carboxylate 2G
3S ##STR00298## (2S)-tert-butyl 4-benzyl-2- methyl-3-oxo-1-oxa-4,9-
diazaspiro[5.6]dodecane- 9-carboxylate 2G
Intermediate 3T: tert-Butyl
4-ethyl-2,2-dimethyl-3-oxo-1-oxa-4,9-diazaspiro[5.6]dodecane-9-carboxylat-
e
##STR00299##
[0464] A solution of intermediate 3J (3.95 g, 12.1 mmol) in dry THF
(17 mL) was cooled to 0.degree. C. After slow addition of LDA
solution (16.1 mL, 1.5M in THF/n-heptane/ethylbenzene, 24.2 mmol),
the reaction mixture was stirred at 0.degree. C. for 30 min.
Iodomethane (2.26 mL, 36.3 mmol) was then added and the reaction
mixture was stirred at 0-6.degree. C. for further 60 min. Again,
LDA solution (16.1 mL, 1.5M in THF/n-heptane/ethylbenzene, 24.2
mmol) was slowly added and the reaction mixture was stirred at
0.degree. C. for 30 min. Additional iodomethane (2.26 mL, 36.3
mmol) was then added and the reaction mixture was stirred at
0-5.degree. C. for additional 60 min to achieve full conversion.
NH.sub.4Cl sat solution was then added, and the aqueous phase was
extracted three times with ethyl acetate. The combined organic
phases were dried over Na.sub.2SO.sub.4, filtered and concentrated
under vacuum. The residue was purified by flash chromatography,
silica gel, gradient DCM to MeOH/DCM (1:4) to give the title
compound (1.18 g, 29% yield)
Intermediate 4A:
10-Ethyl-4-oxa-7,10-diazadispiro[2.1.3.3]undecan-11-one acetate
##STR00300##
[0466] A mixture of intermediate 3C (0.226 g, 0.62 mmol), AcOH
(0.071 mL, 1.25 mmol) and palladium (25 mg, 10% wt on carbon) in
methanol (3 mL) was stirred under 3 bars of H.sub.2 at r.t. for 1
day. The catalyst was filtered off and the solvent was removed
under vacuum to give a mixture of the title compound and
diphenylmethane (0.221 g crude, 0.160 g theoretical weight,
estimated quant yield), used in the next step without further
purification.
[0467] This method was used for the preparation of intermediates
4B-4F using suitable starting materials:
TABLE-US-00011 INT Structure Chemical name s.m. 4B ##STR00301##
10-benzyl-4-oza-7,10- diazadispiro[2.1.3.3]undecan- 11-one acetate
3H 4C ##STR00302## (R)-8-ethyl-6-methyl-5- oxa-2,8-
diazaspiro[3.5]nonan-7- one acetate 3N 4D ##STR00303##
(S)-8-ethyl-6-methyl-5- oxa-2,8- diazaspiro[3.5]nonan-7- one
acetate 3O 4E ##STR00304## (R)-8-isopropyl-6-methyl- 5-oxa-2,8-
diazaspiro[3.5]nonan-7- one acetate 3P 4F ##STR00305##
(S)-8-isopropyl-6-methyl- 5-oxa-2,8- diazaspiro[3.5]nonan-7- one
acetate 3Q
Intermediate 5A: tert-Butyl
12-benzyl-4-oxa-7,12-diazadispiro[2.1.5.3]tridecane-7-carboxylate
##STR00306##
[0469] To a solution of intermediate 3F (7.90 g, 20.4 mmol) in THF
(40 mL), borane-THF complex solution (51.1 mL, 1M in THF, 51.1
mmol) was added dropwise. The reaction mixture was heated at
65.degree. C. for 2 h. After cooling to 0-5.degree. C., 1M NaOH
aqueous solution (40 mL) was carefully added. The mixture was then
heated to reflux for 2 h. and then stirred at r.t. overnight. The
layers were separated and the aqueous phase was extracted with
ethyl acetate. The organic phases were combined, dried over
MgSO.sub.4, filtered and concentrated to dryness to give the title
compound (6.85 g, 90% yield).
[0470] This method was used for the preparation of intermediates
5B-5C using suitable starting materials:
TABLE-US-00012 INT Structure Chemical name s.m. 5B ##STR00307##
tert-butyl 13-benzyl-4- oxa-8,13- diazadispiro[2.1.6.3]tetradecane-
8-carboxylate 3G 5C ##STR00308## tert-butyl 4-benzyl-2,2-
dimethyl-1-oxa-4,9- diazaspiro[5.8]dodecane- 9-carboxylate 3K
[0471] The same method is used for the preparation of intermediates
5D-5E using suitable starting materials:
TABLE-US-00013 5D ##STR00309## (2R)-tert-butyl 4-benzyl-2-
methyl-1-oxa-4,9- diazaspiro[5.6]dodecane- 9-carboxylate 3R 5E
##STR00310## (2S)-tert-butyl 4-benzyl-2- methyl-1-oxa-4,9-
diazaspiro[5.6]dodecane- 9-carboxylate 3S
[0472] Following the method described for the preparation of
Intermediate 4A, Intermediates 6A-6C were prepared using suitable
starting materials:
TABLE-US-00014 INT Structure Chemical name s.m. 6A ##STR00311##
tert-butyl 4-oxa-7,12- diazadispiro[2.1.5.3]tridecane-
7-carboxylate acetate 5A 6B ##STR00312## tert-butyl 4-oxa-8,13-
diazadispiro[2.1.6.3]tetradecane- 8-carboxylate acetate 5B 6C
##STR00313## tert-butyl 2,2- dimethyl-1-oxa-4,9-
diazaspiro[5.6]dodecane- 9-carboxylate acetate 5C
[0473] Following the method described for the preparation of
Intermediate 4A, Intermediates 6D-6E are prepared using suitable
starting materials:
TABLE-US-00015 6D ##STR00314## (2R)-tert-butyl 2- methyl-1-oxa-4,9-
diazaspiro[5.6]dodecane- 9-carboxylate acetate 5D 6E ##STR00315##
(2S)-tert-butyl 2- methyl-1-oxa-4,9- diazaspiro[5.6]dodecane-
9-carboxylate acetate 5E
Intermediate 7A: tert-Butyl
12-benzoyl-4-oxa-7,12-diazadispiro[2.1.5.3]tridecane-7-carboxylate
##STR00316##
[0475] To a solution of intermediate 6A (1.78 g, 5.20 mmol) in
dichloromethane (21 mL) at 0-5.degree. C., triethylamine (1.09 mL,
7.80 mmol) and benzoyl chloride (0.72 mL, 6.24 mmol) were added
dropwise. The reaction mixture was stirred at r.t. for 2 h.
NaHCO.sub.3 sat solution was then added, and the aqueous phase was
extracted with dichloromethane. The organic phases were combined,
washed with aqueous 1M NaOH solution, dried over MgSO.sub.4,
filtered and concentrated under vacuum to give the title compound
(1.74 g, 87% yield).
[0476] This method was used for the preparation of intermediates
7B-7D using suitable starting materials:
TABLE-US-00016 INT Structure Chemical name s.m. 7B ##STR00317##
tert-butyl 13-benzoyl-4- oxa-8,13- diazadispiro[2.1.6.3]
tetradecane-8- carboxylate 6B 7C ##STR00318## tert-butyl
4-benzoyl-2,2- dimethyl-1-oxa-4,9- diazaspiro[5.6] dodecane-9-
carboxylate 6C
[0477] The same method is used for the preparation of intermediates
7D-7E using suitable starting materials:
TABLE-US-00017 7D ##STR00319## (2R)-tert-butyl 4-benzoyl-
2-methyl-1-oxa-4,9- diazaspiro[5.6] dodecane-9- carboxylate 6D 7E
##STR00320## (2S)-tert-butyl 4-benzoyl- 2-methyl-1-oxa-4,9-
diazaspiro[5.6] dodecane-9- carboxylate 6E
SYNTHESIS OF EXAMPLES
Example 1:
12-Ethyl-7-isopentyl-4-oxa-7,12-diazadispiro[2.1.5.3]tridecan-1-
3-one
##STR00321##
[0478] Step 1.
12-Ethyl-4-oxa-7,12-diazadispiro[2.1.5.3]tridecan-13-one
trifluoroacetate
[0479] To a solution of intermediate 3A (904 mg, 2.79 mmol) in DCM
(9 mL), trifluoroacetic acid (2.15 mL, 27.9 mmol) was added, and
the reaction mixture was stirred at r.t. for 2 h. The solvent was
evaporated to dryness to give the title compound as a crude product
(1.66 g, 57 wt %, quant yield), that was used in the following step
without further purification.
Step 2. Title Compound
[0480] A mixture of the crude product obtained in step 1 (0.175 g,
57 wt %, 0.296 mmol), 1-bromo-3-methylbutane (0.057 mL, 0.47 mmol)
and K.sub.2CO.sub.3 (0.204 g, 1.48 mmol) in ACN (2 mL) was heated
at 80.degree. C. in a sealed tube overnight. 1M NaOH aqueous
solution was added, and the reaction mixture was extracted with
ethyl acetate. The organic phases were combined, washed with brine,
dried over MgSO.sub.4, filtered and concentrated to dryness. The
residue was purified by flash chromatography, silica gel, gradient
DCM to MeOH:DCM (1:4) to give the title compound (52 mg, 60%
yield).
[0481] HPLC retention time (method A): 3.75 min; MS: 295.2
(M+H).
[0482] This method was used for the preparation of examples 2-10
using suitable starting materials:
TABLE-US-00018 Ret time MS EX Structure Chemical name (min) (M + H)
2 ##STR00322## 12-ethyl-7-phenethyl-4-oxa- 7,12-
diazadispiro[2.1.5.3] tridecan-13-one 3.85 (method A) 329.2 3
##STR00323## 13-ethyl-8-phenethyl-4-oxa- 8,13-
diazadispiro[2.1.6.3] tetradecan-14-one 3.3 (method A) 343.2 4
##STR00324## 13-ethyl-8-isopentyl-4-oxa- 8,13- diazaspiro[2.1.6.3]
tetradecan-14-one 2.66 (method A) 309.2 5 ##STR00325##
7-benzyl-10-ethyl-4-oxa- 7,10- diazadispiro[2.1.3.3] undecan-11-one
3.17 (method A) 301.1 6 ##STR00326## 10-ethyl-7-isopentyl-4-oxa-
7,10- diazadispiro[2.1.3.3] undecan-11-one 3.13 (method A) 267.2 7
##STR00327## 7-phenethyl-12-phenyl-4- oxa-7,12-
diazadispiro[2.1.5.3] tridecan-13-one 5.18 (method B) 377.2 8
##STR00328## 7-isopentyl-12-phenyl-4-oxa- 7,12-
diazadispiro[2.1.5.3] tridecan-13-one 5.29 (method B) 343.2 9
##STR00329## 8-phenethyl-13-phenyl-4- oxa-8,13-
diazadispiro[2.1.6.3] tetradecan-14-one 4.7 (method B) 391.2 10
##STR00330## 8-isopentyl-13-phenyl-4-oxa- 8,13-
diazadispiro[2.1.6.3] tetradecan-14-one 4.2 (method B) 357.2
Example 11:
7-Benzyl-12-ethyl-4-oxa-7,12-diazadispiro[2.1.5.3]tridecan-13-one
##STR00331##
[0484] To a solution of the crude product obtained in step 1 of
example 1 (0.175 g, 57 wt %, 0.296 mmol) in dry THF (3.5 mL),
benzaldehyde (0.045 mL, 0.44 mmol) was added. The reaction mixture
was stirred at r.t. for 15 min. and then sodium
triacetoxyborohydride (0.272 g, 1.39 mmol) was added in portions.
The resulting mixture was stirred at r.t. overnight. Water and
concentrated NH.sub.3 were carefully added and the mixture was
extracted with ethyl acetate. The organic phases were combined,
washed with brine, dried over Na.sub.2SO.sub.4, filtered and
concentrated to dryness. The residue was purified by flash
chromatography, silica gel, gradient DCM to MeOH:DCM (1:4) to give
the title compound (43 mg, 48% yield).
[0485] HPLC retention time: 3.78 min (method A); MS: 315.2
(M+H).
[0486] This method was used for the preparation of examples 12-15
using suitable starting materials:
TABLE-US-00019 Ret time MS EX Structure Chemical name (min) (M + H)
12 ##STR00332## 8-benzyl-13-ethyl-4-oxa- 8,13-
diazadispiro[2.1.6.3] tetradecan-14-one 3.44 (method A) 329.2 13
##STR00333## 7-benzyl-10-ethyl-4-oxa- 7,10- diazadispiro[2.1.3.3]
undecan-11-one 2.96 (method A) 287.1 14 ##STR00334##
8-benzyl-13-phenyl-4-oxa- 8,13- diazadispiro[2.1.6.3]
tetradecan-14-one 4.84 (method B) 377.2 15 ##STR00335##
7-benzyl-12-phenyl-4-oxa- 7,12- diazadispiro[2.1.5.3]
tridecan-13-one 5.09 (method B) 363.2
Example 16:
13-Ethyl-8-phenethyl-4-oxa-8,13-diazadispiro[2.1.6.3]tetradecan
##STR00336##
[0488] To a solution of Example 3 (131 mg, 0.38 mmol) in THF (0.5
mL), cooled at 0.degree. C., lithium aluminium hydride solution
(1.15 mL, 1M in THF, 1.15 mmol) was added dropwise. The reaction
mixture was stirred at 50.degree. C. overnight, then NaHCO.sub.3
sat aqueous solution was added, and the aqueous phase was extracted
with ethyl acetate. The organic phases were combined, washed with
water, dried over MgSO.sub.4, filtered and concentrated to dryness.
The residue was purified by flash chromatography, silica gel,
gradient DCM to MeOH:DCM (1:4) to give the title compound (70 mg,
56% yield).
[0489] HPLC retention time: 3.32 min (method A); MS: 329.2
(M+H).
[0490] This method was used for the preparation of examples 17-23
using suitable starting materials:
TABLE-US-00020 Ret time MS EX Structure Chemical name (min) (M + H)
17 ##STR00337## 7-benzyl-12-ethyl-4-oxa- 7,12-
diazadispiro[2.1.5.3] tridecane 3.91 (method A) 301.2 18
##STR00338## 13-ethyl-8-phenethyl-4- oxa-8,13-
diazadispiro[2.1.6.3] tetradecane 3.75 (method A) 315.2 19
##STR00339## 7-phenethyl-12-phenyl-4- oxa-7,12-
diazadispiro[2.1.5.3] tridecane 6.01 (method B) 363.2 20
##STR00340## 7-isopentyl-12-phenyl-4- oxa-7,12-
diazadispiro[2.1.5.3] tridecane 6.00 (method B) 329.2 21
##STR00341## 8-benzyl-13-phenyl-4-oxa- 8,13- diazadispiro[2.1.6.3]
tetradecane 5.76 (method B) 363.2 22 ##STR00342##
8-phenethyl-13-phenyl-4- oxa-8,13- diazadispiro[2.1.6.3]
tetradecane 5.62 (method B) 377.2 23 ##STR00343##
7-benzyl-12-phenyl-4-oxa- 7,12- diazadispiro[2.1.5.3] tridecane
6.02 (method B) 349.2
[0491] The method described in Example 1 was used for the
preparation of examples 24-54 using suitable starting
materials:
TABLE-US-00021 Ret time MS EX Structure Chemical name (min) (M + H)
24 ##STR00344## (7-phenethyl-4-oxa- 7,12- diazadispiro[2.1.5.3]
tridecan-12-yl)(phenyl) methanone 5.03 (method B) 391.2 25
##STR00345## (7-isopentyl-4-oxa- 7,12- diazadispiro[2.1.5.3]
tridecan-12-yl)(phenyl) methanone 4.94 (method B) 357.2 26
##STR00346## (7-isobutyl-4-oxa-7,12- diazadispiro[2.1.5.3]
tridecan-12-yl)(phenyl) methanone 5.14 (method B) 343.2 27
##STR00347## (8-phenethyl-4-oxa- 8,13- diazadispiro[2.1.6.3]
tetradecan-13-yl)(phenyl) methanone 4.43 (method B) 405.2 28
##STR00348## (8-isopentyl-4-oxa- 8,13- diazadispiro[2.1.6.3]
tetradecan-13-yl)(phenyl) methanone 3.93 (method B) 371.2 29
##STR00349## (8-isobutyl-4-oxa-8,13- diazadispiro[2.1.6.3]
tetradecan-13-yl)(phenyl) methanone 3.82 (method B) 357.2 30
##STR00350## 4-ethyl-2,2-dimethyl-9- phenethyl-1-oxa-4,9-
diazaspiro[5.6]dodecan- 3-one 3.96 (method B) 345.2 31 ##STR00351##
4-ethyl-9-isopentyl-2,2- dimethyl-1-oxa-4,9-
diazaspiro[5.6]dodecan-3- one 3.35 (method B) 311.3 32 ##STR00352##
4-ethyl-9-isobutyl-2,2- dimethyl-1-oxa-4,9-
diazaspiro[5.6]dodecan-3- one 3.24 (method B) 297.2 33 ##STR00353##
10-benzyl-7-phenethyl- 4-oxa-7,10- diazadispiro[2.1.3.3]
undecan-11-one 4.65 (method B) 363.1 34 ##STR00354##
(2,2-dimethyl-9- phenethyl-1-oxa-4,9- diazaspiro[5.6]dodecan-4-
yl)(phenyl)methanone 5.03 (method C) 407.1 35 ##STR00355##
10-ethyl-7-(2- isopropoxyethyl)-4-oxa- 7,10- diazadispiro[2.1.3.3]
undecan-11-one 3.40 (method C) 283.1 36 ##STR00356##
(R)-8-ethyl-2-isopentyl-6- methyl-5-oxa-2,8-
diazaspiro[3.5]nonan-7- one 3.89 (method C) 255.1 37 ##STR00357##
(S)-8-ethyl-2-isopentyl-6- methyl-5-oxa-2,8-
diazaspiro[3.5]nonan-7- one 3.88 (method C) 255.2 38 ##STR00358##
(R)-8-ethyl-2-isobutyl- 6-methyl-5-oxa-2,8- diazaspiro[3.5]nonan-7-
one 3.56 (method C) 241.1 39 ##STR00359## (S)-8-ethyl-2-isobutyl-6-
methyl-5-oxa-2,8- diazaspiro[3.5]nonan-7- one 3.56 (method C) 241.1
40 ##STR00360## (R)-2-isopentyl-8- isopropyl-6-methyl-5-oxa-
2,8-diazaspiro[3.5]nonan- 7-one 4.21 (method C) 269.2 41
##STR00361## (S)-2-isopentyl-8- isopropyl-6-methyl-5-oxa-
2,8-diazaspiro[3.5]nonan- 7-one 4.21 (method C) 269.2 42
##STR00362## (R)-2-isobutyl-8- isopropyl-6-methyl-5-oxa-
2,8-diazaspiro[3.5]nonan- 7-one 3.92 (method C) 255.1 43
##STR00363## (S)-2-isobutyl-8- isopropyl-6-methyl-5-oxa-
2,8-diazaspiro[3.5]nonan- 7-one 3.92 (method C) 255.2 44
##STR00364## (S)-2-(3,3-dimethylbutyl)-8- isopropyl-6-methyl-5-oxa-
2,8-diazaspiro[3.5]nonan- 7-one 4.48 (method C) 283.2 45
##STR00365## (R)-2-(3,3-dimethylbutyl)- 8-isopropyl-6-methyl-5-
oxa-2,8- diazaspiro[3.5]nonan-7- one 4.48 (method C) 283.2 46
##STR00366## (2R,6S)-4-ethyl-9- isopentyl-2-methyl-1-oxa- 4,9-
diazaspiro[5.6]dodecan-3- one 3.65 (method C) 297.2 47 ##STR00367##
(2R,6R)-4-ethyl-9- isopentyl-2-methyl-1-oxa- 4,9-
diazaspiro[5.6]dodecan-3- one 3.59 (method C) 297.2 48 ##STR00368##
(2S,6S)-4-ethyl-9- isopentyl-2-methyl-1-oxa- 4,9-
diazaspiro[5.6]dodecan-3- one 3.58 (method C) 297.2 49 ##STR00369##
(2S,6R)-4-ethyl-9- isopentyl-2-methyl-1-oxa- 4,9-
diazaspiro[5.6]dodecan-3- one 3.60 (method C) 297.2 50 ##STR00370##
(9-(2-isopropoxyethyl)-2,2- dimethyl-1-oxa-4,9-
diazaspiro[5.6]dodecan-4- yl)(phenyl)methanone 4.38 (method C)
389.2
[0492] The method described in Example 11 was used for the
preparation of examples 55-50 and 55-77 using suitable starting
materials:
TABLE-US-00022 Ret time MS EX Structure Chemical name (min) (M + H)
55 ##STR00371## (7-benzyl-4-oxa-7,12- diazadispiro[2.1.5.3]
tridecan-12-yl)(phenyl) methanone 4.85 (method B) 377.2 56
##STR00372## (8-benzyl-4-oxa-8,13- diazadispiro[2.1.6.3]
tetradecan-13-yl)(phenyl) methanone 4.57 (method B) 391.2 57
##STR00373## 9-benzyl-4-ethyl-2,2- dimethyl-1-oxa-4,9-
diazaspiro[5.6]dodecan-3- one 4.07 (method B) 331.2 58 ##STR00374##
4-((4-ethyl-2,2-dimethyl-3- oxo-1-oxa-4,9-
diazaspiro[5.6]dodecan-9- yl)methyl)benzonitrile 4.58 (method C)
356.2 59 ##STR00375## (2R,6S)-9-benzyl-4-ethyl- 2-methyl-1-oxa-4,9-
diazaspiro[5.6]dodecan-3- one 4.27 (method C) 317.1 60 ##STR00376##
(2R,6R)-9-benzyl-4-ethyl- 2-methyl-1-oxa-4,9-
diazaspiro[5.6]dodecan-3- one 4.16 (method C) 317.1 61 ##STR00377##
(2S,6S)-9-benzyl-4-ethyl- 2-methyl-1-oxa-4,9-
diazaspiro[5.6]dodecan-3- one 4.17 (method C) 317.2 62 ##STR00378##
(2S,6R)-9-benzyl-4-ethyl- 2-methyl-1-oxa-4,9-
diazaspiro[5.6]dodecan-3- one 4.26 (method C) 317.1 63 ##STR00379##
(2R,6S)-4-ethyl-9-(4- fluorobenzyl)-2-methyl-1- oxa-4,9-
diazaspiro[5.6]dodecan-3- one 4.45 (method C) 335.1 64 ##STR00380##
(2R,6R)-4-ethyl-9-(4- fluorobenzyl)-2-methyl-1- oxa-4,9-
diazaspiro[5.6]dodecan-3- one 4.34 (method C) 335.1 65 ##STR00381##
(2S,6S)-4-ethyl-9-(4- fluorobenzyl)-2-methyl-1- oxa-4,9-
diazaspiro[5.6]dodecan-3- one 4.37 (method C) 335.1 66 ##STR00382##
(2S,6R)-4-ethyl-9-(4- fluorobenzyl)-2-methyl-1- oxa-4,9-
diazaspiro[5.6]dodecan-3- one 4.45 (method C) 335.1 67 ##STR00383##
4-(((2R,6S)-4-ethyl-2- methyl-3-oxo-1-oxa-4,9-
diazaspiro[5.6]dodecan-9- yl)methyl)benzonitrile 4.29 (method C)
342.1 68 ##STR00384## 4-(((2R,6R)-4-ethyl-2-
methyl-3-oxo-1-oxa-4,9- diazaspiro[5.6]dodecan-9-
yl)methyl)benzonitrile 4.24 (method C) 342.1 69 ##STR00385##
4-(((2S,6S)-4-ethyl-2- methyl-3-oxo-1-oxa-4,9-
diazaspiro[5.6]dodecan-9- yl)methyl)benzonitrile 4.25 (method C)
342.2 70 ##STR00386## 4-(((2S,6R)-4-ethyl-2-
methyl-3-oxo-1-oxa-4,9- diazaspiro[5.6]dodecan-9-
yl)methyl)benzonitrile 4.29 (method C) 342.1 71 ##STR00387##
8-benzyl-13-methyl-4-oxa- 8,13- diazadispiro[2.1.6.3]
tetradecan-14-one 4.14 (method C) 315.1 72 ##STR00388##
8-(4-fluorobenzyl)-13- methyl-4-oxa-8,13- diazadispiro[2.1.6.3]
tetradecan-14-one 4.32 (method C) 333.1 73 ##STR00389##
4-((13-methyl-14-oxo-4- oxa-8,13- diazadispiro[2.1.6.3]
tetradecan-8-yl)methyl) benzonitrile. 4.15 (method C) 340.1 74
##STR00390## (S)-8-ethyl-6-methyl-2- neopentyl-5-oxa-2,8-
diazaspiro[3.5]nonan-7- one 4.26 (method C) 255.2 75 ##STR00391##
(R)-8-ethyl-6-methyl-2- neopentyl-5-oxa-2,8-
diazaspiro[3.5]nonan-7- one 4.26 (method C) 255.1 76 ##STR00392##
(S)-8-isopropyl-6- methyl-2-neopentyl-5-oxa-
2,8-diazaspiro[3.5]nonan- 7-one 4.61 (method C) 269.2 77
##STR00393## (R)-8-isopropyl-6- methyl-2-neopentyl-5-oxa-
2,8-diazaspiro[3.5]nonan- 7-one 4.62 (method C) 269.2
[0493] The method described in Example 11 is used for the
preparation of examples 51-54 using suitable starting
materials:
TABLE-US-00023 51 ##STR00394## ((2S,6R)-9-isopentyl-2-
methyl-1-oxa-4,9- diazaspiro[5.6]dodecan- 4-yl)(phenyl) methanone
52 ##STR00395## ((2S,6S)-9-isopentyl-2- methyl-1-oxa-4,9-
diazaspiro[5.6]dodecan- 4-yl)(phenyl) methanone 53 ##STR00396##
((2R,6R)-9-isopentyl-2- methyl-1-oxa-4,9- diazaspiro[5.6]dodecan-
4-yl)(phenyl) methanone 54 ##STR00397## ((2R,6S)-9-isopentyl-2-
methyl-1-oxa-4,9- diazaspiro[5.6]dodecan- 4-yl)(phenyl)
methanone
[0494] The method described in Example 16 was used for the
preparation of examples 78-90 using suitable starting
materials:
TABLE-US-00024 Ret time MS EX Structure Chemical name (min) (M + H)
78 ##STR00398## 7,12-dibenzyl-4-oxa-7,12- diazadispiro[2.1.5.3]
tridecane(*) 6.16 (method B) 363.2 79 ##STR00399##
12-benzyl-7-phenethyl-4- oxa-7,12- diazadispiro[2.1.5.3]
tridecane(*) 6.18 (method B) 377.2 80 ##STR00400##
12-benzyl-7-isopentyl-4- oxa-7,12- diazadispiro[2.1.5.3]
tridecane(*) 6.00 (method B) 343.3 81 ##STR00401##
12-benzyl-7-isobutyl-4- oxa-7,12- diazadispiro[2.1.5.3]
tridecane(*) 6.48 (method B) 329.2 82 ##STR00402##
8,13-dibenzyl-4-oxa-8,13- diazadispiro[2.1.6.3] tetradecane(*) 6.00
(method B) 377.2 83 ##STR00403## 13-benzyl-8-phenethyl-4- oxa-8,13-
diazadispiro[2.1.6.3] tetradecane(*) 5.66 (method B) 391.2 84
##STR00404## 13-benzyl-8-isopentyl-4- oxa-8,13-
diazadispiro[2.1.6.3] tetradecane(*) 5.17 (method B) 357.3 85
##STR00405## 13-benzyl-8-isobutyl-4- oxa-8,13-
diazadispiro[2.1.6.3] tetradecane(*) 5.23 (method B) 343.2 86
##STR00406## 9-benzyl-4-ethyl-2,2- dimethyl-1-oxa-4,9-
diazaspiro[5.6]dodecane 5.45 (method B) 317.2 87 ##STR00407##
4-ethyl-2,2-dimethyl-9- phenethyl-1-oxa-4,9-
diazaspiro[5.6]dodecane 5.16 (method B) 331.2 88 ##STR00408##
4-ethyl-9-isopentyl-2,2- dimethyl-1-oxa-4,9-
diazaspiro[5.6]dodecane 4.46 (method B) 297.3 89 ##STR00409##
4-ethyl-9-isobutyl-2,2- dimethyl-1-oxa-4,9- diazaspiro[5.6]dodecane
4.32 (method B) 283.2 90 ##STR00410## 10-benzyl-7-phenethyl-4-
oxa-7,10- diazadispiro[2.1.3.3] undecane 4.87 (method B) 349.2
(*) The corresponding benzoyl precursor was used as starting
material.
Example 91:
(7-Phenethyl-4-oxa-7,10-diazadispiro[2.1.3.3]undecan-10-yl)(phenyl)methan-
one
##STR00411##
[0495] Step 1. 7-Phenethyl-4-oxa-7,10-diazadispiro[2.1.3.3]undecane
acetate
[0496] The preparation procedure described for the synthesis of
Intermediate 4A was used for the preparation of the title compound,
using Example 90 as starting material.
Step 2. Title Compound
[0497] Following the method described for the preparation of
Intermediate 7A but starting from the product obtained in Step 1,
the title compound was obtained.
[0498] HPLC retention time (method C): 4.95 min; MS: 363.1
(M+H).
Examples 92 and 93:
(R)-8-benzyl-13-ethyl-4-oxa-8,13-diazadispiro[2.1.3]tetradecan-14-one
and
(S)-8-benzyl-13-ethyl-4-oxa-8,13-diazadispiro[2.1.6.3]tetradecan-14-one
##STR00412##
[0500] Starting from Example 12, a chiral preparative HPLC
separation (column: Chiralcel OJ; temperature: ambient; flow: 8
ml/min; eluent n-Heptane/EtOH+0.5% DEA 98/2 v/v) was carried out to
give the title compounds.
Examples 94 and 95:
(R)-2,2-dimethyl-9-phenethyl-1-oxa-4,9-diazaspiro[5.6]dodecan-4-yl)(pheny-
l)methanone and
(S)-(2,2-dimethyl-9-phenethyl-1-oxa-4,9-diazaspiro[5.6]dodecane-4-yl)(phe-
nyl)methanone
##STR00413##
[0502] Starting from Example 34, a chiral preparative HPLC
separation (column: Chiralcel OJ; temperature: ambient; flow: 8
mL/min; eluent n-Heptane/EtOH 95/5 v/v) was carried out to give the
title compounds.
Examples 96 and 97:
(R)-8-isopentyl-4-oxa-8,13-diazadispiro[2.1.6.3]tetradecan-13
yl)(phenyl)methanone and
(S)-(8-isopentyl-4-oxa-8,13-diazadispiro[2.1.6.3]tetradecan-13-yl)(phenyl-
)methanone
##STR00414##
[0504] Starting from Example 28, a chiral preparative HPLC
separation is carried out to give the title compounds.
Table of Examples with Binding to the .sigma..sub.1-Receptor:
Biological Activity
Pharmacological Study
Human .sigma..sub.1 Receptor Radioligand Assay
[0505] To investigate binding properties of test compounds to human
.sigma..sub.1 receptor, transfected HEK-293 membranes and
[.sup.3H](+)-pentazocine (Perkin Elmer, NET-1056), as the
radioligand, were used. The assay was carried out with 7 .mu.g of
membrane suspension, 5 nM of [.sup.3H](+)-pentazocine in either
absence or presence of either buffer or 10 .mu.M Haloperidol for
total and non-specific binding, respectively. Binding buffer
contained Tris-HCl 50 mM at pH 8. Plates were incubated at
37.degree. C. for 120 minutes. After the incubation period, the
reaction mix was then transferred to MultiScreen HTS, FC plates
(Millipore), filtered and plates were washed 3 times with ice-cold
10 mM Tris-HCL (pH7.4). Filters were dried and counted at
approximately 40% efficiency in a MicroBeta scintillation counter
(Perkin-Elmer) using EcoScint liquid scintillation cocktail
Results:
[0506] As this invention is aimed at providing a compound or a
chemically related series of compounds which act as ligands of the
.sigma..sub.1 receptor it is a very preferred embodiment in which
the compounds are selected which act as ligands of the
.sigma..sub.1 receptor and especially compounds which have a
binding expressed as K.sub.i which is preferably <1000 nM, more
preferably <500 nM, even more preferably <100 nM.
[0507] The following scale as been adopted for representing the
binding to the the .sigma..sub.1 receptor expressed as K.sub.i:
[0508] +K.sub.i-.sigma..sub.1>=500 nM [0509]
++K.sub.i-.sigma..sub.1<500 nM [0510]
+++K.sub.i-.sigma..sub.1<100 nM
[0511] All compounds prepared in the present application exhibit
binding to the .sigma..sub.1 receptor, in particular the following
binding results are shown:
TABLE-US-00025 EXAMPLE K.sub.i-.sigma..sub.1 1 + 2 + 3 +++ 4 +++ 5
++ 6 +++ 7 ++ 8 ++ 9 +++ 10 +++ 11 + 12 +++ 13 + 14 +++ 15 + 16 +++
17 + 18 + 19 +++ 20 +++ 21 +++ 22 +++ 23 ++ 24 + 25 ++ 26 + 27 +++
28 +++ 29 ++ 30 +++ 31 ++ 32 ++ 33 +++ 34 +++ 35 + 36 + 37 + 38 +
39 + 40 + 41 + 42 + 43 + 44 + 45 + 46 + 47 + 48 + 49 + 50 + 55 + 56
+++ 57 +++ 58 + 59 + 60 + 61 + 62 + 63 + 64 + 65 + 66 + 67 + 68 +
69 + 70 + 71 + 72 + 73 + 74 + 75 + 76 + 77 + 78 +++ 79 +++ 80 +++
81 +++ 82 +++ 83 +++ 84 +++ 85 +++ 86 +++ 87 +++ 88 +++ 89 +++ 90
+++ 91 + 92 +++ 93 +++ 94 ++ 95 ++
* * * * *